cas 362-75-4, 2',3'-O-Isopropylideneadenosine

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Copper-Catalyzed Intramolecular Alkoxylation of Purine Nucleosides: One-Step Synthesis of 5′-O,8-Cyclopurine Nucleosides
A novel copper-catalyzed intramolecular dehydrogenative alkoxylation of purine nucleosides has been developed successfully, providing the 5′-O,8-cyclopurine nucleosides in one-step with a yield up to 90%. The method, which utilized an inexpensive CuCl catalyst and a di-tert-butyl peroxide (DTBP) oxidant was suitable in a broad substrate scope and proceeded well even in gram scale.
Yu, Mingwu,Wang, Zhiqian,Hu, Junbin,Li, Shunlai,Du, Hongguang
p. 9446 - 9453
(2015)
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Protein arginine allylation and subsequent fluorophore targeting
Protein allylation and fluorophore targeting: Arginine residues of the yeast nuclear ribonucleoprotein Npl3 were extensively modified by Hmt1-catalyzed allylation reaction with allyl-SAM as the allyl group donor. The allylated protein was further treated with tetrazole compounds under UV irradiation, leading to formation of protein-attached fluorescent products.
Zhang, Yixin,Pan, Yanbo,Yang, Wei,Liu, Wujun,Zou, Hanfa,Zhao, Zongbao K.
p. 1438 - 1443
(2013)
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Synthesis and cytostatical evaluation of cytidine- and adenosine-5'-hexadecylphosphate and their phosphonate analogs
Four phospholipid conjugates containing the non-cytotoxic nucleosides cytidine and adenosine were prepared by condensation reactions, and their cytotoxic activity was tested in vitro against the human immortalized mammary epithelial cell H184 A1N4, the human mammary tumor cells MaTu and MCF7 and the B lymphoblast cell line Daudi. The synthesized compounds showed considerable activity towards H184 A1N4, MaTu and Daudi cells, but they were not effective against MCF7 cells. The phosphorus moiety - either monophosphate or monophosphonate - does not influence the effectiveness of the phospholipid derivatives in the case of the solid tumor cell lines and H184 A1N4. The leukemic Daudi cell line is strongly sensitive towards the different types of ester as well as to the type of the nucleoside component. Adenosine-5'-hexadecylphosphate proved to be the most potent compound among the substances prepared (IC50: 9.0 μmol).
Brachwitz,Bergmann,Thomas,Berdel,Langen,Wollny
p. 143 - 149
(1997)
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5'2-(N -aminoacyl)-sulfonamido-5'2-deoxyadenosine: Attempts for a stable alternative for aminoacyl-sulfamoyl adenosines as aaRS inhibitors
Synthesis of aminoacyl-sulfamoyl adenosines (aaSAs) and their peptidyl conjugates as aminoacyl tRNA synthetase (aaRS) inhibitors remains problematic due to the low yield of the aminoacylation and the subsequent conjugation reaction causing concomitant formation of a cyclic adenosine derivative. In an effort to reduce this undesirable side reaction, we aimed to prepare the corresponding aminoacyl sulfonamide (aaSoA) analogues as more stable alternatives for aaSA derivatives. Deletion of the 5'2-oxygen in aaSA analogues should render the C-5'2 less electrophilic and therefore improve the stability of the aminoacyl sulfamate analogues. We therefore synthesized six sulfonamides and compared their activity against the respective aaSA analogues. However, except for the aspartyl derivative, the new compounds are not able to inhibit the corresponding aaRS. Possible reasons for this loss of activity are discussed by modeling and comparison of the newly synthesized aaSoA derivatives with their parent aaSA analogues.
Gadakh, Bharat,Smaers, Simon,Rozenski, Jef,Froeyen, Mathy,Van Aerschot, Arthur
p. 227 - 236
(2015)
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Charge-Tagged DNA Radicals in the Gas Phase Characterized by UV/Vis Photodissociation Action Spectroscopy
Adenosine radicals tagged with a fixed-charge group were generated in the gas phase and structurally characterized by tandem mass spectrometry, deuterium labeling, and UV/Vis action spectroscopy. Experimental results in combination with Born–Oppenheimer molecular dynamics, ab initio, and excited-state calculations led to unambiguous assignment of adenosine radicals as N-7 hydrogen atom adducts. The charge-tagged radicals were found to be electronically equivalent to natural DNA nucleoside radicals.
Dang, Andy,Liu, Yue,Ture?ek, Franti?ek,Urban, Jan
p. 7772 - 7777
(2020)
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Potential utility of adenosine 5′-ester prodrugs to enhance its plasma half-life: Synthesis and molecular docking studies
Adenosine, the adenine nucleoside, has demonstrated various pharmacological properties related to the treatment of relevant clinical diseases. With respect to this, one of the most fascinating biological activities of adenosine is its capacity for reversing hepatic fibrosis, which has been established in several in vitro and in vivo studies. Although adenosine seems to be a privileged compound, it lacks of metabolic stability to be considered as a drug candidate. For this reason, in this preliminary study, six prodrugs were developed in order to enhance the plasma half-life of adenosine, in which the esterification at 5′ position of adenosine was considered. According to previous works, the increase in steric hindrance at this position could develop unfavorable interactions inside adenosine deaminase (ADA) catalytic domain, which is reported as the main enzyme implicated in adenosine metabolism. Besides, molecular docking was employed to verify if the hindrance at carbinol group in the prodrugs is enough to diminish its oxidation and also to predict if compounds would be metabolized by a promiscuous esterase. Finally, the in vitro assays corroborated the theoretical findings and also indicated that the compounds are less metabolized than adenosine by ADA; in the case of compounds containing proline and thioproline progroups (4d and 4e, respectively), the reduction was more than three-fold of decrease.
Hernández-Vázquez, Eduardo,Chagoya, Victoria
p. 2325 - 2335
(2015)
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Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1
Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.
Shah, Rachit,Strom, Alexander,Zhou, Andrew,Maize, Kimberly M.,Finzel, Barry C.,Wagner, Carston R.
p. 780 - 784
(2016)
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Purine derivative and preparation method and application thereof
The invention discloses a purine derivative and a preparation method and application thereof, belongs to the technical field of medicines, and designs and synthesizes a series of purine derivatives and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs of the purine derivatives. Experiments show that the compound has outstanding anti-cell proliferation activity and DOT1L enzyme inhibition effect, shows good tumor growth inhibition activity in a tumor transplantation tumor model, and has a good application prospect.
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Paragraph 0166; 0211-0213

(2021/06/26)

Chemical Proteomics Approach for Profiling the NAD Interactome
Nicotinamide adenine dinucleotide (NAD+) is a multifunctional molecule. Beyond redox metabolism, NAD+ has an equally important function as a substrate for post-translational modification enzymes, the largest family being the poly-ADP-ribose polymerases (PARPs, 17 family members in humans). The recent surprising discoveries of noncanonical NAD (NAD+/NADH)-binding proteins suggests that the NAD interactome is likely larger than previously thought; yet, broadly useful chemical tools for profiling and discovering NAD-binding proteins do not exist. Here, we describe the design, synthesis, and validation of clickable, photoaffinity labeling (PAL) probes, 2- and 6-ad-BAD, for interrogating the NAD interactome. We found that 2-ad-BAD efficiently labels PARPs in a UV-dependent manner. Chemical proteomics experiments with 2- and 6-ad-BAD identified known and unknown NAD+/NADH-binding proteins. Together, our study shows the utility of 2- and 6-ad-BAD as clickable PAL NAD probes.
?ileikyt?, Justina,Sundalam, Sunil,David, Larry L.,Cohen, Michael S.
supporting information
p. 6787 - 6791
(2021/05/29)

NOVEL HISTONE METHYLTRANSFERASE INHIBITORS
The present invention relates to novel compounds of formula (I) as defined herein. The compounds are inhibitors of histone methyltransferases of the seven-beta-strand family, in particular of KMT9.
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(2021/04/01)

Tightly linked morpholino-nucleoside chimeras: new, compact cationic oligonucleotide analogues
The polyanionic phosphodiester backbone of nucleic acids contributes to high nuclease sensitivity and low cellular uptake and is therefore a major obstacle to the biological application of native oligonucleotides. Backbone modifications, particularly charge alterations is a proven strategy to provide artificial oligonucleotides with improved properties. Here, we describe the synthesis of a new type of oligonucleotide analogues consisting of a morpholino and a ribo- or deoxyribonucleoside in which the 5′-amino group of the nucleoside unit provides the nitrogen of the morpholine ring. The synthetic protocol is compatible with trityl and dimethoxytrityl protecting groups and azido functionality, and was extended to the synthesis of higher oligomers. The chimeras are positively charged in aqueous medium, due to theN-alkylated tertiary amine structure of the morpholino unit.
Batta, Gyula,Bege, Miklós,Bereczki, Ilona,Borbás, Anikó,Debreczeni, Nóra,Herczeg, Mihály,Herczegh, Pál
supporting information
p. 8711 - 8721
(2021/10/22)

A pan-inhibitor for protein arginine methyltransferase family enzymes
Protein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs that tethers a thioadenosine and various substituted guanidino groups through a propyl linker. Compound II757 exhibits a half-maximal inhibition concentration (IC50 ) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC50 = 5 nM). The kinetic study demonstrated that II757 competitively binds at the SAM binding site of PRMT1. Notably, II757 is selective for PRMTs over a panel of other methyltransferases, which can serve as a general probe for PRMTs and a lead for further optimization to increase the selectivity for individual PRMT.
Iyamu, Iredia D.,Al-Hamashi, Ayad A.,Huang, Rong
(2021/06/11)

Kinase-Inhibitory Nucleoside Derivatives from the Pacific Bryozoan Nelliella nelliiformis
Marine organisms are a valuable source of bioactive natural products, yet bryozoan invertebrates have been relatively understudied. Herein, we report nelliellosides A and B, new secondary metabolites of the Pacific bryozoan Nelliella nelliiformis, found using NMR-guided isolation. Their structures, including absolute configurations, were elucidated using spectroscopic and chromatographic techniques. Total synthesis of the natural products and four analogues was also achieved, in addition to an assessment of their biological activity, especially kinase inhibition.
Bracegirdle, Joe,Gordon, Dennis P.,Harvey, Joanne E.,Keyzers, Robert A.
p. 547 - 551
(2020/03/19)

Sulfonium-Based Homolytic Substitution Observed for the Radical SAM Enzyme HemN
Sulfur-based homolytic substitution (SH reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S-adenosyl-l-methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di-(5′-deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical-mediated SH reaction on the sulfonium center of SAM. The sulfonium-based SH reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium-based SH reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes.
Deng, Zixin,Ding, Wei,Ji, Wenjuan,Ji, Xinjian,Mandalapu, Dhanaraju,Sun, Peng,Zhang, Qi
supporting information
p. 8880 - 8884
(2020/04/01)

SYNTHESIS OF 8-CHLOROADENOSINE DERIVATIVES INCLUDING NUC-9701
The present invention generally relates to a novel process for the preparation of 8-chloroadenosine derivatives, and particularly NUC-9701(8-chloroadenosine-5'-O- [naphthyl(benzyloxy-L-alaninyl)] phosphate) an anticancer ProTide of 8-chloroadenosine.
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(2020/07/14)

Dissecting modular synthases through inhibition: A complementary chemical and genetic approach
Modular synthases, such as fatty acid, polyketide, and non-ribosomal peptide synthases (NRPSs), are sophisticated machineries essential in both primary and secondary metabolism. Various techniques have been developed to understand their genetic background and enzymatic abilities. However, uncovering the actual biosynthetic pathways remains challenging. Herein, we demonstrate a pipeline to study an assembly line synthase by interrogating the enzymatic function of each individual enzymatic domain of BpsA, a NRPS that produces the blue 3,3′-bipyridyl pigment indigoidine. Specific inhibitors for each biosynthetic domain of BpsA were obtained or synthesized, and the enzymatic performance of BpsA upon addition of each inhibitor was monitored by pigment development in vitro and in living bacteria. The results were verified using genetic mutants to inactivate each domain. Finally, the results complemented the currently proposed biosynthetic pathway of BpsA.
Vickery, Christopher R.,McCulloch, Ian P.,Sonnenschein, Eva C.,Beld, Joris,Noel, Joseph P.,Burkart, Michael D.
supporting information

(2019/12/24)

Novel adenosine-derived inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase
We have found cyclophane-type adenosine derivatives having p-quinone amide moieties (1 and 2) as weak inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase (CpIMPDH) from the Hokkaido University Chemical Library via the luciferase-based high-throughput screening. To obtain more potent inhibitors, we synthesized four new derivatives free from cyclophane rings (3–6). The N-H derivatives 3 and 5 showed more potent activities (24.4 and 11.1 μM, respectively) in the presence of dithiothreitol (DTT), whereas the N-methyl derivative 4 indicated more potent activity (2.1 μM) without DTT. Conformational analysis of compounds 3 and 4 suggested that N-H amide 3 binds to IMP-binding site in the DTT mediated manner.
Shigetomi, Kengo,Sarwono, Albertus Eka Yudistira,Ichikawa, Satoshi,Ubukata, Makoto
p. 934 - 942
(2019/07/18)

Purine compound containing bicyclic group, and preparation method thereof
The invention provides a purine compound containing a bicyclic group which is shown as a formula (I) and a formula (II) and a pharmaceutically acceptable salt, and a preparation method thereof. The compound is an inhibitor of histone methyltransferase DOT1L, and can be used for treating diseases caused by the abnormity of enzyme activity, such as tumor.
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Paragraph 0091; 0095; 0096

(2019/10/01)

Adenosine diphosphate ribose compound, preparation method and biological activity thereof
The invention discloses an adenosine diphosphate ribose compound, which has a general formula shown as (I), wherein the definitions of all substituents are detailed in the specification. In addition,the invention also discloses a preparation method and application of the compound. The adenosine diphosphate ribose (ADPR) structural analogue provided by the invention has specific TRPM2 (transient receptor potential melastatin 2) inhibitory activity.
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Paragraph 0050-0054

(2019/01/24)

Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily
The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl- (IleRS)and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of Class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA)compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 ? crystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavourable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the Class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency.
De Ruysscher, Dries,Pang, Luping,De Graef, Steff,Nautiyal, Manesh,De Borggraeve, Wim M.,Rozenski, Jef,Strelkov, Sergei V.,Weeks, Stephen D.,Van Aerschot, Arthur
p. 252 - 264
(2019/05/02)

Compositions and Methods for Reverse Automated Nucleic Acid Synthesis
Methods for reverse automated nucleic acid synthesis, and 5′-H-phosphonates suitable for use in the same, as well as methods for making 5′-H-phosphonates, are described.
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Paragraph 0106-0107

(2019/10/29)

Synthesis, structure and bioactivity of primary sulfamate-containing natural products
Here we report the synthesis of natural products (NPs) 5′-O-sulfamoyl adenosine 1 and 5′-O-sulfamoyl-2-chloroadenosine 2. As primary sulfamates these compounds represent an uncommon class of NPs, furthermore there are few NPs known that contain a N–S bond. Compounds 1 and 2 were evaluated for inhibition of carbonic anhydrases (CA), a metalloenzyme family where the primary sulfamate is known to coordinate to the active site zinc and form key hydrogen bonds with adjacent CA active site residues. Both NPs were good to moderate CA inhibitors, with compound 2 a 20–50-fold stronger CA inhibitor (Ki values 65–234 nM) than compound 1. The protein X-ray crystal structures of 1 and 2 in complex with CA II show that it is not the halogen-hydrophobic interactions that give compound 2 a greater binding energy but a slight movement in orientation of the ribose ring that allows better hydrogen bonds to CA residues. Compounds 1 and 2 were further investigated for antimicrobial activity against a panel of microbes relevant to human health, including Gram-negative bacteria (4 strains), Gram-positive bacteria (1 strain) and yeast (2 strains). Antimicrobial activity and selectivity was observed. The minimum inhibitory concentration (MIC) of NP 1 was 10 μM against Gram-positive Staphylococcus aureus and NP 2 was 5 μM against Gram-negative Escherichia coli. This is the first time that NP primary sulfamates have been assessed for inhibition and binding to CAs, with systematic antimicrobial activity studies also reported.
Mujumdar, Prashant,Bua, Silvia,Supuran, Claudiu T.,Peat, Thomas S.,Poulsen, Sally-Ann
supporting information
p. 3009 - 3013
(2018/04/30)

SULFAMIDE AND SULFAMATE INHIBITORS OF hHint1
Embodiments provide, among things, compounds of the formula I and methods for using such compounds to reduce pain (e.g., neuronal pain), treat a mammal's addiction to nicotine or anti-pain drugs, and increase a mammal's sensitivity to drugs that bind MOR or NMDAR.
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Paragraph 0138; 0139

(2018/03/25)

An effective and convenient synthesis of cordycepin from adenosine
Cordycepin is a purine nucleoside analog with potent and diverse biological activities. Herein, we designed two methods to synthesize cordycepin. One method mainly converted the 3′-OH group into an iodide group and further dehalogenation to yield the final product. Although this method presented a short synthetic procedure, the synthesis had a low overall yield, resulting in only 13.5% overall yield. To improve the overall yield of cordycepin, another synthetic route was studied, which consisted of four individual steps: (1) 5′-OH protection (2) esterification (3) -O-tosyl (-OTs) group removal (4) deprotection. The key step in the synthetic method involved the conversion of 5′-O-triphenylmethyladenosine to 3′-O-tosyl-5′-O-triphenylmethyladenosine, using LiAlH4 as reducing agent. The main advantages of this route were an acceptable total product yield and the commercial availability of all starting materials. The optimal reaction conditions for each step of the route were identified. The overall yield of cordycepin obtained from adenosine as the starting material was 36%.
Huang, Shen,Liu, Hui,Sun, Yanhua,Chen, Jian,Li, Xiufang,Xu, Jiangfeng,Hu, Yuwei,Li, Yuqing,Deng, Zhiwei,Zhong, Shian
p. 149 - 160
(2018/01/17)

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5′-diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole-cell patch-clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC50 of 5.7 and 5.4?μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure–activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.
Luo, Xiao,Li, Meng,Zhan, Kaiyu,Yang, Wei,Zhang, Lihe,Wang, KeWei,Yu, Peilin,Zhang, Liangren
p. 552 - 566
(2017/11/21)

NOVEL 6-6 BICYCLIC AROMATIC RING SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS
The present invention relates novel 6-6 bicyclic aromatic ring substituted nucleoside analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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(2017/03/14)

Synthesis and antiviral evaluation of novel N-6 substituted adenosine analogues
A series of adenosine analogues were synthesized and their biological evaluation was tested against Coxsackie virus B3 (CVB3) and Herpes simplex virus type 1(HSV-1) in HEp-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were calculated. Analogues with piperazine derivatives 8b showed promising activities against CVB3 with a lower IC50value and higher selectivity index, their efficacy was better than that of the commercialized medicine, Ribavirin. These described adenosine analogues exhibit potent antiviral activities against several viruses, and offer new leads for further development.
Hao, Youwu,Zhou, Gaohui,Wu, Wei,Zhang, Yang,Tao, Liming,Yao, Jianhua,Xu, Wenping
supporting information
p. 190 - 193
(2016/12/27)

SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS
The present invention relates novel substituted nucleoside analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 93; 94

(2017/09/27)

Construction of a library of structurally diverse ribonucleopeptides with catalytic groups
Functional screening of structurally diverse libraries consisting of proteins or nucleic acids is an effective method to obtain receptors or aptamers with unique molecular recognition characteristics. However, further modification of these selected receptors to exert a newly desired function is still a challenging task. We have constructed a library of structurally diverse ribonucleopeptides (RNPs) that are modified with a catalytic group, in which the catalytic group aligns with various orientations against the ATP binding pocket of RNA subunit. As a proof-of-principle, the screening of the constructed RNP library for the catalytic reaction of ester hydrolysis was successfully carried out. The size of both the substrate-binding RNA library and the catalytic group modified peptide library are independently expandable, and thus, the size of RNPs library could be enlarged by a combination of these two subunits. We anticipate that the library of functionalized and structurally diverse RNPs would be expanded for various other catalytic reactions.
Tamura, Tomoki,Nakano, Shun,Nakata, Eiji,Morii, Takashi
p. 1 - 7
(2017/03/08)

Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme
The investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5′,5′-Difluoro-5′-deoxyadenosine 7 (F2DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5′-fluoro-5′-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F2DA 7 was found, however, not to undergo the enzyme catalysed reaction with l-selenomethionine, unlike FDA 2, which undergoes reaction with l-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F2DA 7 and tartrate was solved to 1.8 ?, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed.
Thompson, Stephen,McMahon, Stephen A.,Naismith, James H.,O'Hagan, David
supporting information
p. 37 - 41
(2015/12/08)

A selective inhibitor of the UFM1-activating enzyme, UBA5
Protein conjugation with ubiquitin and ubiquitin-like small molecules, such as UFM1, is important for promoting cancer cell survival and proliferation. Herein, the development of the first selective micromolar inhibitor of the UBA5 E1 enzyme that initiates UFM1 protein conjugation is described. This organometallic inhibitor incorporates adenosine and zinc(II)cyclen within its core scaffold and inhibits UBA5 noncompetitively and selectively over other E1 enzymes and a panel of human kinases. Furthermore, this compound selectively impedes the cellular proliferation (above 50?μM) of cancer cells containing higher levels of UBA5. This inhibitor may be used to further probe the intracellular role of the UFM1 pathway in disease progression.
da Silva, Sara R.,Paiva, Stacey-Lynn,Bancerz, Matthew,Geletu, Mulu,Lewis, Andrew M.,Chen, Jijun,Cai, Yafei,Lukkarila, Julie L.,Li, Honglin,Gunning, Patrick T.
p. 4542 - 4547
(2016/08/24)

An axial nucleoside asymmetric modified silicon phthalocyanine and its preparation method and application
The invention discloses axial nucleoside asymmetrically-modified silicon phthalocyanine and a preparation method and application thereof, belonging to the preparation field of a photodynamic medicine or a photosensitizer. The axial nucleoside asymmetrically-modified silicon phthalocyanine disclosed by the invention can be applied to photodynamic treatment, photodynamic diagnosis or photodynamic disinfection as a photosensitizer, has the structural characteristic of axial asymmetric substitution, and shows good amphipathicity and excellent photodynamic activity.
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Paragraph 0069; 0070

(2016/10/10)

In Situ Proteome Profiling and Bioimaging Applications of Small-Molecule Affinity-Based Probes Derived from DOT1L Inhibitors
DOT1L is the sole protein methyltransferase that methylates histone H3 on lysine 79 (H3K79), and is a promising drug target against cancers. Small-molecule inhibitors of DOT1L such as FED1 are potential anti-cancer agents and useful tools to investigate the biological roles of DOT1L in human diseases. FED1 showed excellent in vitro inhibitory activity against DOT1L, but its cellular effect was relatively poor. In this study, we designed and synthesized photo-reactive and "clickable" affinity-based probes (AfBPs), P1 and P2, which were cell-permeable and structural mimics of FED1. The binding and inhibitory effects of these two probes against DOT1L protein were extensively investigated in vitro and in live mammalian cells (in situ). The cellular uptake and sub-cellular localization properties of the probes were subsequently studied in live-cell imaging experiments, and our results revealed that, whereas both P1 and P2 readily entered mammalian cells, most of them were not able to reach the cell nucleus where functional DOT1L resides. This offers a plausible explanation for the poor cellular activity of FED1. Finally with P1/P2, large-scale cell-based proteome profiling, followed by quantitative LC-MS/MS, was carried out to identify potential cellular off-targets of FED1. Amongst the more than 100 candidate off-targets identified, NOP2 (a putative ribosomal RNA methyltransferase) was further confirmed to be likely a genuine off-target of FED1 by preliminary validation experiments including pull-down/Western blotting (PD/WB) and cellular thermal shift assay (CETSA). Minimalist "clickable" probes: Small-molecule probes P1 and P2 based on FED1 (a known DOT1L inhibitor) were developed and successfully used in experiments including live-cell imaging, in situ proteome profiling, and off-target identification (see scheme).
Zhu, Biwei,Zhang, Hailong,Pan, Sijun,Wang, Chenyu,Ge, Jingyan,Lee, Jun-Seok,Yao, Shao Q.
supporting information
p. 7824 - 7836
(2016/06/09)

Synthesis and Pharmacological Evaluation of Novel Adenine-Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents
This work deals with the design, synthesis, and evaluation of the cardioprotective properties of a number of novel hybrid compounds combining the adenine nucleus with a suitable H2S slow-releasing moiety, coupled via a stable ether bond. The H2S release rate of the hybrids and their ability to increase cGMP were estimated in vitro. The most promising derivatives 4 and 11, both containing 4-hydroxythiobenzamide moiety as H2S donor, were selected for further in vivo evaluation. Their ability to release H2S in vivo was recorded using a new fully validated UPLC-DAD method. Both compounds reduced significantly the infarct size when administered at the end of sustained ischemia. Mechanistic studies showed that they conferred enhanced cardioprotection compared to adenine or 4-hydroxythiobenzamide. They activate the PKG/PLN pathway in the ischemic myocardium, suggesting that the combination of both pharmacophores results in synergistic cardioprotective activity through the combination of both molecular pathways that trigger cardioprotection.
Lougiakis, Nikolaos,Papapetropoulos, Andreas,Gikas, Evangelos,Toumpas, Spyridon,Efentakis, Panagiotis,Wedmann, Rudolf,Zoga, Anastasia,Zhou, Zhongmin,Iliodromitis, Efstathios K.,Skaltsounis, Alexios-Leandros,Filipovic, Milos R.,Pouli, Nicole,Marakos, Panagiotis,Andreadou, Ioanna
p. 1776 - 1790
(2016/03/22)

Mechanistic studies of the radical S-adenosylmethionine enzyme DesII with TDP-D-fucose
DesII is a radical S-adenosylmethionine (SAM) enzyme that catalyzes the C4-deamination of TDP-4-amino-4,6-dideoxyglucose through a C3 radical intermediate. However, if the C4 amino group is replaced with a hydroxy group (to give TDP-quinovose), the hydroxy group at C3 is oxidized to a ketone with no C4-dehydration. It is hypothesized that hyperconjugation between the C4 C-N/O bond and the partially filled p orbital at C3 of the radical intermediate modulates the degree to which elimination competes with dehydrogenation. To investigate this hypothesis, the reaction of DesII with the C4-epimer of TDP-quinovose (TDP-fucose) was examined. The reaction primarily results in the formation of TDP-6-deoxygulose and likely regeneration of TDP-fucose. The remainder of the substrate radical partitions roughly equally between C3-dehydrogenation and C4-dehydration. Thus, changing the stereochemistry at C4 permits a more balanced competition between elimination and dehydrogenation.
Ko, Yeonjin,Ruszczycky, Mark W.,Choi, Sei-Hyun,Liu, Hung-Wen
supporting information
p. 860 - 863
(2015/03/05)

Design, synthesis, and kinetic analysis of potent protein N-terminal methyltransferase 1 inhibitors
The protein N-terminal methyltransferase 1 (NTMT1) methylates the α-N-terminal amines of proteins. NTMT1 is upregulated in a variety of cancers and knockdown of NTMT1 results in cell mitotic defects. Therefore, NTMT1 inhibitors could be potential anticancer therapeutics. This study describes the design and synthesis of the first inhibitor targeting NTMT1. A novel bisubstrate analogue (NAM-TZ-SPKRIA) was shown to be a potent inhibitor (Ki = 0.20 μM) for NTMT1 and was selective versus protein lysine methyltransferase G9a and arginine methyltransferase 1. NAM-TZ-SPKRIA was found to exhibit a competitive inhibition pattern for both substrates, and mass spectrometry experiments revealed that the inhibitor substantially suppressed the methylation progression. Our results demonstrate the feasibility of using a triazole group to link an S-adenosyl-l-methionine analog with a peptide substrate to construct bisubstrate analogues as NTMT1 potent and selective inhibitors. This study lays a foundation to further discover small molecule NTMT1 inhibitors to interrogate its biological functions, and suggests a general strategy for the development of selective protein methyltransferase inhibitors. This journal is
Zhang, Gang,Richardson, Stacie Lynn,Mao, Yunfei,Huang, Rong
supporting information
p. 4149 - 4154
(2015/04/14)

UBA5 INHIBITORS
The present disclosure relates to compounds of the Formula (I), which are UBA5 inhibitors.
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Paragraph 00107; 00110; 00111

(2015/12/18)

α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.
Bhattarai, Sanjay,Freundlieb, Marianne,Pippel, Jan,Meyer, Anne,Abdelrahman, Aliaa,Fiene, Amelie,Lee, Sang-Yong,Zimmermann, Herbert,Yegutkin, Gennady G.,Str?ter, Norbert,El-Tayeb, Ali,Müller, Christa E.
supporting information
p. 6248 - 6263
(2015/08/24)

Analogues of the natural product sinefungin as inhibitors of EHMT1 and EHMT2
A series of analogues of the natural product sinefungin lacking the amino acid moiety was synthesized and probed for their ability to inhibit EHMT1 and EHMT2. This study led to inhibitors 3b and 4d of methyltransferase activity of EHMT1 and EHMT2 and it demonstrates that such analogues constitute an interesting scaffold to develop selective methyltransferase inhibitors. Surprisingly, the inhibition was not competitive toward AdoMet.
Devkota, Kanchan,Lohse, Brian,Liu, Qing,Wang, Ming-Wei,Staerk, Dan,Berthelsen, Jens,Clausen, Rasmus Praetorius
supporting information
p. 293 - 297
(2014/05/06)

Specific enrichment of nonribosomal peptide synthetase module by an affinity probe for adenylation domains
We targeted the development of an affinity probe for adenylation (A) domains that can facilitate enrichment, identification, and quantification of A domain-containing modules in nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) hybrids and NRPSs. A 5′-O-sulfamoyladenosine (AMS) non-hydrolyzable analogue of adenosine monophosphate (AMP) has been reported as a scaffold for the design of inhibitors exhibiting tight binding of adenylation enzymes. Here we describe the application of an affinity probe for A domains. Our synthetic probe, a biotinylated l-Phe-AMS (l-Phe-AMS-biotin) specifically targets the A domains in NRPS modules that activates l-Phe to an aminoacyladenylate intermediate in both recombinant NRPS enzyme systems and whole proteomes.
Ishikawa, Fumihiro,Kakeya, Hideaki
supporting information
p. 865 - 869
(2014/02/14)

SELECTIVE INHIBITORS OF HISTONE METHYLTRANSFERASE DOT1L
Structure and mechanism based design was used to design potent ribose containing inhibitors of DOT1L with IC50 values as low as 38 nM. These ribose containing inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1.
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Paragraph 0056; 0063

(2014/04/18)

1-(Hydroxyacetyl)pyrene a new fluorescent phototrigger for cell imaging and caging of alcohols, phenol and adenosine
1-(Hydroxyacetyl)pyrene has been introduced as a new fluorescent phototrigger for alcohols and phenols. Alcohols and phenols were protected as their corresponding carbonate esters by coupling with fluorescent phototrigger, 1-(hydroxyacetyl)pyrene. Photophysical studies of caged carbonates showed that they all exhibited strong fluorescence properties. Irradiation of the caged carbonates by visible light (≥410 nm) in aqueous acetonitrile released the corresponding alcohols or phenols in high chemical (95-97%) and quantum (0.17-0.21) yields. The mechanism for the photorelease was proposed based on Stern-Volmer quenching experiments and solvent effect studies. Importantly, 1-(hydroxyacetyl)pyrene showed as a phototrigger for rapid photorelease of the biologically active molecule adenosine. In vitro biological studies revealed that 1-(hydroxyacetyl)pyrene has good biocompatibility, cellular uptake property and cell imaging ability. The Royal Society of Chemistry and Owner Societies 2012.
Jana, Avijit,Saha, Biswajit,Ikbal, Mohammed,Ghosh, Sudip Kumar,Singh, N. D. Pradeep
p. 1558 - 1566
(2013/02/26)

Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L
Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with Ki values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC50 values of 4-11 μM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-l-methionine) but not the substrate nucleosome.
Anglin, Justin L.,Deng, Lisheng,Yao, Yuan,Cai, Guobin,Liu, Zhen,Jiang, Hong,Cheng, Gang,Chen, Pinhong,Song, Yongcheng,Dong, Shuo
supporting information
p. 8066 - 8074,9
(2020/09/15)

Efficient synthesis of exo-N-carbamoyl nucleosides: Application to the synthesis of phosphoramidate prodrugs
An efficient protection protocol for the 6-exo-amino group of purine nucleosides with various chloroformates was developed utilizing N-methylimidazole (NMI). The reaction of an exo-N6-group of adenosine analogue 1 with alkyl/and aryl chloroformates under optimized conditions provided the N6-carbamoyl adenosines (2a-j) in good to excellent yields. The reaction of N6-Cbz-protected nucleosides (5a-c) with phenyl phosphoryl chloride (7) using t-BuMgCl followed by catalytic hydrogenation afforded the corresponding phosphoramidate pronucleotides (8a-c) in excellent yield.
Cho, Jong Hyun,Coats, Steven J.,Schinazi, Raymond F.
supporting information; experimental part
p. 2488 - 2491
(2012/08/27)

Synthesis and in vitro stability of nucleoside 5′-phosphonate derivatives
Nucleoside derivatives are largely synthesized and tested to investigate their influence on platelet aggregation. It's well known that P2Y receptors play an important role in the regulation of platelet function and, as consequence, in controlling atherothrombotic events. The research of compounds that antagonize P2Y1 and, in particular, P2Y12 receptors is of great interest in the aim to obtain platelet aggregation inhibitors that are effective in the prevention and treatment of arterial thrombosis. In this study we present the synthesis and in vitro metabolic stability in human blood and rat liver homogenate of a new class of nucleoside derivatives, in particular 5′-phosphonate adenosine, inosine, guanosine and thioadenosine analogues also modified at the ribose moiety. On the basis of the results obtained we can hypothesize compounds 4 and 18 to have in vivo a relatively high stability.
Vertuani, Silvia,Baldisserotto, Anna,Varani, Katia,Borea, Pier Andrea,De Marcos Maria Cruz, Bonache,Ferraro, Luca,Manfredini, Stefano,Dalpiaz, Alessandro
supporting information; experimental part
p. 202 - 209
(2012/09/07)

Styryl conjugated coumarin caged alcohol: Efficient photorelease by either one-photon long wavelength or two-photon NIR excitation
The synthesis and photorelease properties of a new phototrigger for alcohols are described. Compared to ester 4 caged by the reported [7-(diethylamino)coumarin-4-yl]methoxycarbonyl (DEACM) phototrigger, the caged ester 3 shows an efficient single-photon photolysis efficiency upon irradiation of long wavelength light (λ = 475 nm) and a stronger two-photon photolysis sensitivity with 800 nm laser light. Its promising properties and the efficient photorelease of adenosine make it very useful as a caging group for biological applications.
Bao, Chunyan,Fan, Guanshui,Lin, Qiuning,Li, Bo,Cheng, Shuiyu,Huang, Qi,Zhu, Linyong
supporting information; experimental part
p. 572 - 575
(2012/03/26)

MODULATORS OF HISTONE METHYLTRANSFERASE, AND METHODS OF USE THEREOF
Disclosed are compounds, pharmaceutical compositions containing the compounds, and the uses of the compounds and compositions as modulators of histone methyltransferases, and for treating diseases influenced by modulation of histone methyltransferase activity.
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Page/Page column 193-194

(2012/06/30)

Identification of NAE inhibitors exhibiting potent activity in leukemia cells: Exploring the structural determinants of NAE specificity
MLN4924 is a selective inhibitor of the NEDD8-activating enzyme (NAE) and has advanced into clinical trials for the treatment of both solid and hematological malignancies. In contrast, the structurally similar compound 1 (developed by Millennium: The Takeda Oncology Company) is a pan inhibitor of the E1 enzymes NAE, ubiquitin activating enzyme (UAE), and SUMO-activating enzyme (SAE) and is currently viewed as unsuitable for clinical use given its broad spectrum of E1 inhibition. Here, we sought to understand the determinants of NAE selectivity. A series of compound 1 analogues were synthesized through iterative functionalization of the purine C6 position and evaluated for NAE specificity. Optimal NAE specificity was achieved through substitution with primary N-alkyl groups, while bulky or secondary N-alkyl substituents were poorly tolerated. When assessed in vitro, inhibitors reduced the growth and viability of malignant K562 leukemia cells. Through this study, we have successfully identified a series of sub-10 nM NAE-specific inhibitors and thereby highlighted the functionalities that promote NAE selectivity.
Lukkarila, Julie L.,Da Silva, Sara R.,Ali, Mohsin,Shahani, Vijay M.,Xu, G. Wei,Berman, Judd,Roughton, Andrew,Dhe-Paganon, Sirano,Schimmer, Aaron D.,Gunning, Patrick T.
supporting information; experimental part
p. 577 - 582
(2011/10/02)

Selective inhibitors of histone methyltransferase DOT1L: Design, synthesis, and crystallographic studies
Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC50 values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L-inhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.
Yao, Yuan,Chen, Pinhong,Diao, Jiasheng,Cheng, Gang,Deng, Lisheng,Anglin, Justin L.,Prasad, B. V. Venkataram,Song, Yongcheng
supporting information; experimental part
p. 16746 - 16749
(2011/12/14)

Comparative inhibitory activity of 3′- and 5′-functionalized nucleosides on ribonuclease A
Modified nucleosides, molecules, functionalized with various polar groups at different positions have been synthesized to rationalize the impact of structural modification on their inhibitory activity. Agarose gel and precipitation assays indicate their improved inhibitory activity on ribonuclease A (RNase A). Kinetic experiments clearly categorize them as competitive inhibitors of RNase A with improved inhibition constant (Ki) values (37 ± 9, 67 ± 6, and 193±7 μM for compounds 10, 3, and 7, respectively). The preferential hydrogen bonding network formation between His-12 and His-119 of RNase A with the polar carboxylic and amino groups of these compounds has been evidenced from the docking studies. The relationship between structural modifications and inhibitory activity of these compounds is further justified in terms of energetics using PEARLS.
Debnath, Joy,Dasgupta, Swagata,Pathak, Tanmaya
experimental part
p. 8257 - 8263
(2011/02/22)

Simple method for fast deprotection of nucleosides by triethylamine- catalyzed methanolysis of acetates in aqueous medium
A straightforward methodology for deacetylation of protected ribonucleosides was developed based on triethylamine-catalyzed solvolysis in aqueous methanol. Reactions are completed in a few minutes under microwave irradiation and the free nucleosides are obtained in high yield after simple evaporation of volatiles. Other important features include the involvement of readily available reagents and the compatibility with diverse functional groups, which make this process very attractive for broad application.
Meier, Lidiane,Monteiro, Gustavo C.,Baldissera, Rodrigo A.M.,Sa?, Marcus Mandolesi
experimental part
p. 859 - 866
(2010/09/11)