- Synthesis and preliminary biological evaluation of two fluoroolefin analogs of largazole inspired by the structural similarity of the side chain unit in psammaplin A
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Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.
- Zhang, Bingbing,Shan, Guangsheng,Zheng, Yinying,Yu, Xiaolin,Ruan, Zhu-Wei,Li, Yang,Lei, Xinsheng
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Read Online
- Synthesis and HDAC inhibitory activity of isosteric thiazoline-oxazole largazole analogs
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The synthesis of an isosteric analog of the natural product and HDAC inhibitor largazole is described. The sulfur atom in the thizaole ring of the natural product has been replaced with an oxygen atom, constituting an oxazole ring. The biochemical activity and cytotoxicity of this species is described.
- Guerra-Bubb, Jennifer M.,Bowers, Albert A.,Smith, William B.,Paranal, Ronald,Estiu, Guillermina,Wiest, Olaf,Bradner, James E.,Williams, Robert M.
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Read Online
- Addition of Sialic Acid to Insulin Confers Superior Physical Properties and Bioequivalence
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Native insulin is susceptible to biophysical aggregation and fibril formation, promoted by manual agitation and elevated temperatures. The safety of the drug and its application to alternative forms of administration could be enhanced through the identification of chemical modifications that strengthen its physical stability without compromising its biological properties. Complex polysialic acids (PSAs) exist naturally and provide a means to enhance the physical properties of peptide therapeutics. A set of insulin analogues site-specifically derivatized with sialic acid were prepared in an overall yield of 50-60%. Addition of a single or multiple sialic acids conferred remarkable enhancement to the biophysical stability of human insulin while maintaining its potency. The time to the onset of fibrillation was extended by more than 10-fold relative to that of the native hormone. These results demonstrate that simplified sialic acid conjugates represent a viable alternative to complex natural PSAs in increasing the stability of therapeutic peptides.
- Kabotso, Daniel E. K.,Kabotso, Daniel E. K.,Smiley, David,Mayer, John P.,Gelfanov, Vasily M.,Perez-Tilve, Diego,Dimarchi, Richard D.,Pohl, Nicola L. B.,Liu, Fa
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p. 6134 - 6143
(2020/07/10)
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- C18-site fluoro Largazole analog, preparation method and application in preparation of antitumor agents
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The invention belongs to the pharmaceutical field, and relates to a preparation method and pharmaceutical application of a fluorinated analogue of natural marine product cyclodepsipeptide (namely natural marine product Largazole) shown in the formula (I). The inhibitory activity test of HDACs in vitro shows that the compound of the invention has a strong and selective inhibitory effect on HDACs. Furthermore, drugs or compositions containing the compound of the present invention can be used to prepare anti-tumor therapeutic agents. The formula is shown in the description.
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Paragraph 0070; 0072-0074
(2019/01/23)
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- A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling
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Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a “fluorine scan” strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs. Unlike other modifications which often led to significant reduction or complete loss of activity as reported in the literature, most of these fluoro thiols have displayed comparable or enhanced activity and selectivity in enzymatic assays. Two of the sulfhydryl esters have also exhibited excellent inhibitory activity in cellular assays with a few selected cell lines. The C19-fluorinated analogue has been further studied by immunoblot analysis, confirming that it is a potent selective class I HDAC inhibitor and supporting that the potent cellular antiproliferative activity is due to HDAC inhibition. The molecular docking study reveals that introducing fluorine at the C19 position does not change the original interactions, but might have made a subtle change in binding conformation, resulting in an obvious improvement in activity.
- Zhang, Bingbing,Liu,Gao, Dingding,Yu, Xiaolin,Wang, Jinlei,Lei, Xinsheng
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supporting information
(2019/09/10)
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- HSP90-TARGETING CONJUGATES AND FORMULATIONS THEREOF
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Conjugates of an active agent attached to a targeting moiety, such as an HSP90 binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
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Paragraph 00380
(2018/07/05)
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- Radical-Mediated Thiol-Ene Strategy: Photoactivation of Thiol-Containing Drugs in Cancer Cells
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Photoactivated drugs provide an opportunity to improve efficacy alongside reducing side-effects in the treatment of severe diseases such as cancer. Described herein is a photoactivation decaging method of isobutylene-caged thiols through a UV-initiated thiol-ene reaction. The method was demonstrated with an isobutylene-caged cysteine, cyclic disulfide-peptide, and thiol-containing drug, all of which were rapidly and efficiently released under mild UV irradiation in the presence of thiol sources and a photoinitiator. Importantly, it is shown that the activity of histone deacetylase inhibitor largazole can be switched off when stapled, but selectively switched on within cancer cells when irradiated with non-phototoxic light.
- Sun, Shuang,Oliveira, Bruno L.,Jiménez-Osés, Gonzalo,Bernardes, Gon?alo J. L.
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supporting information
p. 15832 - 15835
(2018/11/10)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ETHYLIDENE-4,21-BIS(1-METHYLETHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TETRAAZABICYCLO[8.7.6]TRICOS-16-ENE-3, 6, 9, 19, 22-PENTONE
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The present invention is relates to an improved process for the preparation (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I.
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Page/Page column 26; 27
(2017/05/19)
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- Synthesis of Naphthyridine Carbamate Dimer (NCD) Derivatives Modified with Alkanethiol and Binding Properties of G-G Mismatch DNA
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A series of new DNA binding molecules NCD-Cn-SH (n = 3, 4, 5, and 6) is reported, which possesses the NCD (naphthyridine carbamate dimer) domain selectively binding to the G-G mismatch in the 5′-CGG-3′/5′-CGG-3′ sequence and a thiol moiety, which undergoes spontaneous dimerization to (NCD-Cn-S)2 upon oxidation under aerobic conditions. The S-S dimer (NCD-Cn-S)2 produced the 1:1 binding complex with improved thermal stability. The dimer binding to the CGG/CGG DNA showed higher positive cooperativity than the binding of monomer and previously synthesized NCTn derivative. The dimerization of NCD-Cn-SH was selectively accelerated on the CGG repeat DNA but not on the CAG repeat DNA.
- Yamada, Takeshi,Miki, Shouta,Ul'Husna, Anisa,Michikawa, Akiko,Nakatani, Kazuhiko
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p. 4163 - 4166
(2017/08/23)
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- Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics
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A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the production of novel disulfide peptidomimetics in a highly general fashion.
- Vishwanatha, Thimmalapura M.,Bergamaschi, Enrico,D?mling, Alexander
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supporting information
p. 3195 - 3198
(2017/06/23)
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- TARGETED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF
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Nanoparticles and microparticles, and pharmaceutical formulations thereof, containing conjugates of an active agent such as maytansinoid attached to a targeting moiety, such as a somatostatin receptor binding moiety, via a linker have been designed. Such nanoparticles and microparticles can provide improved temporospatial delivery of the active agent and/or improved biodistribution. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided.
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Paragraph 00334
(2017/01/23)
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- NOVEL HDAC INHIBITORS AND METHODS OF TREATMENT USING THE SAME
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Disclosed herein are novel HDAC inhibitors. The HDAC inhibitors may be used in methods of treating cancer. The HDAC inhibitors may be used in methods of treating a neurological disorder.
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Paragraph 000162
(2017/03/21)
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- Fluorinated olefin analogue of marine natural product cyclic depsipeptide as well as preparation method and application of fluorinated olefin analogue
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The invention belongs to the pharmaceutical field and relates to a novel fluorinated olefin analogue of marine natural product cyclic depsipeptide (namely marine natural product Largazole), in particular to a compound shown in the general formula (1) or salt and a preparation method of the compound as well as a drug containing the compound or application of the compound serving as an anti-tumor therapeutic agent.
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Paragraph 0077; 0078; 0079
(2017/07/12)
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- A [...] analogs, its preparation process and its application
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The invention discloses a largazole analogue which contains alkyl disulfide side chains and is represented by formula I, and a preparation method and applications thereof. The largazole analogue possesses relatively high antineoplastic activity and selectivity, can be used for development of antitumor drugs. Raw materials of the largazole analogue are cheap and easily available; and the preparation method is simple, and is a method suitable for industrialization. R in formula represents an alkyl group containing 1 to 8 carbon atoms.
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- Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
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A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-a-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.
- Almaliti, Jehad,Al-Hamashi, Ayad A.,Negmeldin, Ahmed T.,Hanigan, Christin L.,Perera, Lalith,Pflum, Mary Kay H.,Casero, Robert A.,Tillekeratne, L. M. Viranga
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p. 10642 - 10660
(2016/12/16)
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- TARGETED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF
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Nanoparticles and microparticles, and pharmaceutical formulations thereof, containing conjugates of an active agent such as a therapeutic, prophylactic, or diagnostic agent attached to a targeting moiety, such as a somatostatin receptor binding moiety, via a linker have been designed. Such nanoparticles and microparticles can provide improved temporospatial delivery of the active agent and/or improved biodistribution. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer or infectious diseases.
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Paragraph 00364
(2016/01/25)
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- Modular synthesis and biological activity of pyridyl-based analogs of the potent Class i Histone Deacetylase Inhibitor Largazole
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The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein.
- Clausen, Dane J.,Smith, William B.,Haines, Brandon E.,Wiest, Olaf,Bradner, James E.,Williams, Robert M.
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p. 5061 - 5074
(2015/08/03)
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- Study for diastereoselective aldol reaction in flow: synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid, a key component of cyclodepsipeptide HDAC inhibitors
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Abstract Flow synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (5), a key component of cyclodepsipeptide histone deacetylase inhibitors was achieved. An efficient flow system for the synthesis of α, β-unsaturated ester 8 was established using a flow reactor column packed with polymer-supported 1,4-diazabicyclo[2.2.2]octane and a fast mixing accessible flow reactor (Comet X-01). Enal 9 was efficiently prepared by a partial reduction of the α, β-unsaturated ester 8 using diisobutylaluminium hydride in the flow system, and the continuous-flow diastereoselective aldol reaction was performed at low temperature, giving a good yield and diastereoselectivity of the desired aldol 10.
- Doi, Takayuki,Otaka, Hiroyuki,Umeda, Koji,Yoshida, Masahito
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p. 6463 - 6470
(2015/08/18)
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- HDAC Inhibitors as Anti-Cancer Agents
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Largazole analogues, methods of making the same, and methods of using the same, are described.
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Paragraph 0139
(2016/01/15)
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- Total synthesis and stereochemical revision of burkholdac A
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A stereocontrolled total synthesis of burkholdac A was completed, leading to a revision of the reported stereochemistry. Georg Thieme Verlag Stuttgart · New York.
- Liu, Junyang,Ma, Xiao,Liu, Yuqing,Wang, Zhuo,Kwong, Shuqin,Ren, Qi,Tang, Shoubin,Meng, Yi,Xu, Zhengshuang,Ye, Tao
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supporting information; experimental part
p. 783 - 787
(2012/07/03)
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- Total synthesis of spiruchostatin B aided by an automated synthesizer
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The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.
- Fuse, Shinichiro,Okada, Kumiko,Iijima, Yusuke,Munakata, Asami,MacHida, Kazuhiro,Takahashi, Takashi,Takagi, Motoki,Shin-Ya, Kazuo,Doi, Takayuki
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experimental part
p. 3825 - 3833
(2011/06/21)
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- Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation
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The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
- Bhansali, Pravin,Hanigan, Christin L.,Casero, Robert A.,Tillekeratne, L. M. Viranga
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experimental part
p. 7453 - 7463
(2012/01/03)
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- Peptide ligation assisted by an auxiliary attached to amidyl nitrogen
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New thiol-containing auxiliaries were developed for peptide ligation. They were placed at the amidyl N-atom in the second amino acid residue of a peptide fragment. With the new auxiliaries, peptide ligation could be conducted at non-Cys and non-Gly sites. Compared to other recently developed auxiliaries, an important feature of the present design was that the new auxiliaries were generally applicable and readily removable.
- Li, Juan,Cui, Hong-Kui,Liu, Lei
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scheme or table
p. 1793 - 1796
(2010/06/13)
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- Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues
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Largazole 4a and analogues with modifications at the C7 position, as well as 2,4′-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4′-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and α-tubulin acetylation levels and p21WAF1/CIP1 up-regulation in NB4 cells. The activity of the natural product HDACi largazole 4a is not significantly altered by the presence of groups of different size (H, Et, Ph) at C7 on the dihydrothiazole ring.
- Souto, José A.,Vaz, Esther,Lepore, Ilaria,P?ppler, Ann-Christin,Franci, Gianluigi,álvarez, Rosana,Altucci, Lucia,De Lera, ángel R.
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supporting information; scheme or table
p. 4654 - 4667
(2010/10/02)
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- Macrolactamization versus macrolactonization: Total synthesis of FK228, the depsipeptide histone deacetylase inhibitor
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(Chemical Equation Presented) The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.
- Wen, Shijun,Packham, Graham,Ganesan
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scheme or table
p. 9353 - 9361
(2009/04/05)
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- Heterocyclic compounds, method of developing new drug leads and combinatorial libraries used in such method
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The present invention provides according to a first of its aspects, new compounds that have a flexible scaffold with various degrees of conformational restriction and accordingly are useful as drug candidates. These compounds may be used to produce new combinatorial libraries that will permit to screen for and select drug candidates for a variety of uses in human medicine, veterinary medicine and in agriculture.
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- Total Synthesis of the Depsipeptide FR-901375
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The first total synthesis of FR-901375, a novel bicyclic depsipeptide isolated from the fermentation broth of Pseudomonas chloroaphis No. 2522, has been achieved. The synthetic approach involves 13 reaction steps and is achieved in 12% overall yield. The key points in the successful synthetic strategy are a concise asymmetric synthesis of the key building block (3R,4E)-3-hydroxy-7-mercapto-4-heptenoic acid, a mild Mitsunobu macrolactonization step, and an I2-mediated deprotection with concomitant disulfide-bridge formation.
- Chen, Yanping,Gambs, Celine,Abe, Yoshito,Wentworth Jr., Paul,Janda, Kim D.
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p. 8902 - 8905
(2007/10/03)
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