Natural product chemistry. Part <b>159</b>. Two methods for the synthesis of 4‐azaacronycine as a potential antitumor agent

Reisch, J.; Dziemba, P.; Mura, M. La; Rao, A. Raghu Ram

doi:10.1002/jhet.5570300423

Cited by 12 publications

(4 citation statements)

References 11 publications

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“…The 4-chloro-[1,3,5]triazine 4 was synthesized via the reaction of 2,4-dichloro-[1,3,5]triazine 3 16 with Bocprotected aniline 2 under basic conditions (Scheme 1). The required bromide 7 was prepared in a two-step sequence: (1) a Curtius rearrangement 17 of the nicotinic acid 5 with DPPA gave 6, and (2) alkylation of 6 with the silyl-protected bromide gave 7. To our surprise, the palladium-catalyzed Stille coupling reaction 18 (or Suzuki coupling reaction 19 ) of chloride 4 with the organostannane (or organoboron compound) prepared from bromide 7 gave only a trace amount of the coupling product.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

et al. 2005

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On the basis of previous studies, we identified pyrazine-pyridine A as a potent vascular endothelial growth factor inhibitor and pyrimidine-pyridine B as a moderately potent cyclin dependent kinase (CDK) inhibitor. A proposed combination of CGP-60474 and compound B led to the discovery of [1,3,5]triazine-pyridine as a new series of potent CDK inhibitors. Palladium-catalyzed C-C bond formation reactions, particularly the Negishi coupling reaction, were used to assemble various triazine-heteroaryl analogues effectively. Among them, compound 20 displayed high inhibitory potency at CDK1 (IC(50) = 0.021 microM), CDK2, and CDK5 and submicromolar potency at CDK4, CDK6, and CDK7. Compound 20 also displayed high potency at GSK-3beta. It demonstrated potent antiproliferative activity on various tumor cell lines, including HeLa, HCT-116, U937, and A375. When 20 was administered intraperitoneally at 150 and 125 mg/kg to nude mice bearing human A375 xenografts, the compound produced a significant survival increase. Molecular docking studies were conducted in an attempt to enhance the understanding of the observed structure-activity relationship.

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Section: Chemistrymentioning

confidence: 99%

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

et al. 2005

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“…The chloride 3 was synthesized via a palladiumcatalyzed C-N bond formation reaction 25 of 4,6-dichloropyrimidine 1 with 3-chloroaniline followed by Boc protection (Scheme 2). The required organostannane 7 was prepared in three-step sequence: (1) a Curtius rearrangement 26 of the nicotinic acid 4 with DPPA gave 5, (2) alkylation of 5 with the silyl-protected bromide gave 6, (3) a palladium-catalyzed transformation of the organo halide to the organostannane 27 provided 7. The first biheteroaryl target, pyrimidine-pyridine 8, was synthesized by a palladium-catalyzed Stille coupling reaction 28 of halide 3 with organostannane 7 followed by deprotection with TFA (Scheme 2).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Discovery of Pyrazine−Pyridine Biheteroaryl as a Novel Series of Potent Vascular Endothelial Growth Factor Receptor-2 Inhibitors

et al. 2004

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Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C-C bond, C-N bond formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery of a pyrazine-pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound 15, which had IC(50) = 0.084 microM at VEGFR-2, showed very modest selectivity against fibroblast growth factor receptor-2 (IC(50) = 0.21 microM), platelet-derived growth factor receptor (IC(50) = 0.36 microM), and glycogen synthase kinase-3 (IC(50) = 0.478 microM), while it exhibited more than 10-fold selectivity against epidermal growth factor receptor (IC(50) = 1.36 microM) and insulin-R kinase (IC(50) = 1.69 microM). On the other hand, compound 15 exhibited more than 100-fold selectivity against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein kinase; and protein kinase A, Cbeta2, and Cgamma (IC(50) >10 microM). Compound 15 also displayed high inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation (IC(50) = 0.005 microM) and good selectivity against cell lines such as HUVEC, human aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.

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“…It is not at this stage clear whether these three formal 3-monoterpenyl quinoline alkaloids arise from further prenylation of a pyranoquinoline, or by cyclization of a 3-geranylquinoline. The latter pathway is almost certainly involved in the biogenesis of huajiaosimuline ( 64) and (+)zanthosimuline (65), two monoterpenoid pyrano[3,2-c]quinolinone alkaloids isolated from the root bark of Taiwanese Zanthoxylum simulans and characterized with the aid of the usual complement of spectroscopic techniques.21 Racemic (65) was formerly known as a synthetic 1.5 Furoquinoline Alkaloids Dictamnine (66), isolated from Zanthoxylum ailanthoides, completely inhibited platelet aggregation induced by arachidonic acid at a concentration of 100pgml-l, and was also markedly effective in inhibiting platelet aggregation induced by collagen and PAF.28 y-Fagarine (67), haplopine (77), and robustine (78) from Zanthoxylum simulans showed similar behaviour ; in particular, the first two inhibited2, arachidonic acid-induced platelet aggregation completely at 100 pg ml-l.…”

Section: Monoterpenoid Quinoline Alkaloidsmentioning

confidence: 99%

Quinoline, quinazoline, and acridone alkaloids

Michael¹

1995

Nat. Prod. Rep.

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Natural product chemistry. Part 159. Two methods for the synthesis of 4‐azaacronycine as a potential antitumor agent

Cited by 12 publications

References 11 publications

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

Synthesis and Discovery of Pyrazine−Pyridine Biheteroaryl as a Novel Series of Potent Vascular Endothelial Growth Factor Receptor-2 Inhibitors

Quinoline, quinazoline, and acridone alkaloids

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