- 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase
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Six novel 2-amino-4-oxo-5-[(substituted phenyl)sulfanyl]pyrrolo[2,3- d]pyrimidines 7-12 were synthesized as potential inhibitors of thymidylate synthase (TS) and as antitumor and/or antibacterial agents. The analogues contain a 5-thio substituent with a p
- Gangjee, Aleem,Mavandadi, Farahnaz,Kisliuk, Roy L.,McGuire, John J.,Queener, Sherry F.
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- Synthesis of 2-amino-4-oxo-5-substitutedbenzylthiopyrrolo[2,3-d]- pyrimidines as potential inhibitors of thymidylate synthase [1]
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A series of ten novel 2-amino-4-oxo-5-[(substitutedbenzyl)thio]pyrrolo[2,3- d]pyrimidines 2-11 were synthesized as potential inhibitors of thymidylate synthase and as antitumor agents. The analogues contain various electron withdrawing and electron donati
- Gangjee, Aleem,Jain, Hiteshkumar D.,Phan, Jaclyn,Kisliuk, Roy L.
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- Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase
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Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.
- Asami, Tokiko,Furuichi, Hatsuo,Irie, Takayuki,Kashimoto, Shigeki,Kawahata, Wataru,Kiyoi, Takao,Sawa, Masaaki
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p. 14129 - 14141
(2021/10/01)
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- Photochromism of diarylethene-functionalized 7-deazaguanosines
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In a prior report we introduced a novel class of photochromic nucleosides (PCNs) that combine the structural features of adenine with the photochromic properties of diarylethenes. Herein, we translated this concept to the nucleoside guanosine, generating
- Singer, Marco,Nierth, Alexander,Jaeschke, Andres
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supporting information
p. 2766 - 2769
(2013/07/11)
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- Synthesis and evaluation of novel ligands for the histamine H4 receptor based on a pyrrolo[2,3-d]pyrimidine scaffold
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Starting from a known H4R ligand based on a pyrimidine skeleton, a series of novel analogues based on a pyrrolo[2,3-d]pyrimidine scaffold have been prepared. Whereas the original pyrimidine congener shows good affinity at hH4R (Ki = 0.5 μM), its lacks selectivity with a K i value for the hH3R of 1 μM. Within the newly synthesized pyrrolo[2,3-d]pyrimidines, several congeners show Ki values of less than 1 μM at the hH4R and show a much improved selectivity profile. Therefore, these series represent an interesting starting point for the discovery of novel hH4R ligands.
- Gao, Ling-Jie,Schwed, J. Stephan,Weizel, Lilia,De Jonghe, Steven,Stark, Holger,Herdewijn, Piet
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p. 132 - 137
(2013/02/23)
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- Synthesis of new pyrrolo[2,3-d]pyrimidine derivatives and evaluation of their activities against human colon cancer cell lines
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New pyrrolo[2,3-d]Pyrimidines with heteroaryl substitution at 5th position through sulfur linker were synthesized incorporating putative pharmacophoric moieties like benzimidazole and benzothiazole as heteroaryl groups. Cytotoxic effect of all the compounds was carried out on HCT116 colon cancer cell lines. Compounds 6c and 6h with nitrobenzimidazole and pyrimidyl heterocycles attached at 5th position via sulfur were the most potent of all with IC50 values ≈17.6?μM. Among the four compounds tested for apoptosis induction activity, 6c induced apoptosis in a dose dependent manner.
- Tangeda, Saritha Jyostna,Garlapati, Achaiah
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experimental part
p. 1453 - 1458
(2010/06/12)
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- 2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors
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A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}-l-glutamic acid 5 and 11 nonclassical antifolates 6-16 were designed, synthesized, and evaluated as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds 6-16 were synthesized from 20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid 21 followed by saponification gave the classical analog 5. Compound 5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog 5 was a nanomolar inhibitor and remarkably selective inhibitor of Pneumocystis carinii DHFR and Mycobacterium avium DHFR at 263-fold and 2107-fold, respectively, compared to mammalian DHFR. The nonclassical analogs 6-16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.
- Gangjee, Aleem,Jain, Hiteshkumar D.,Phan, Jaclyn,Guo, Xin,Queener, Sherry F.,Kisliuk, Roy L.
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experimental part
p. 953 - 961
(2010/05/02)
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- Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3 H -quinazolin-6-yl)methylprop-2- ynylamino]- N -(3-pyridylmethyl)benzamide (CB-30865) as potent inhibitors of nicotinamide phosphoribosyltransferase (Nampt)
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We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino] -N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C2 of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.
- Lockman, Jeffrey W.,Murphy, Brett R.,Zigar, Daniel F.,Judd, Weston R.,Slattum, Paul M.,Gao, Zhong-Hua,Ostanin, Kirill,Green, Jeremy,McKinnon, Rena,Terry-Lorenzo, Ryan T.,Fleischer, Tracey C.,Boniface, J. Jay,Shenderovich, Mark,Willardsen, J. Adam
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experimental part
p. 8734 - 8746
(2011/02/23)
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- Ricin inhibitors and methods for use thereof
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Ricin A-chain is an N-glycosidase that attacks ribosomal RNA at a highly conserved adenine residue. Crystallographic studies show that not only adenine and formycin, but also pterin-based rings can bind in the ricin active site. For a better understanding
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- 5-Arylthio-Substituted 2-Amino-4-oxo-6-methylpyrrolopyrimidine Antifolates as Thymidylate Synthase Inhibitors and Antitumor Agents
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Classical antifolate inhibitors of thymidylate synthase (TS) often require the reduced folate uptake system in order to exert their antitumor effects.In addition, these analogues are polyglutamylated via the enzyme folylpoly-γ-glutamate synthetase (FPGS),
- Gangjee, Aleem,Devray, Rajesh,McGuire, John J.,Kisliuk, Roy L.
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p. 4495 - 4502
(2007/10/03)
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