ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity.

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development.

A novel, broad-spectrum anticancer compound containing the imidazo[4,5-e][1,3]diazepine ring system.

Synthesis and broad-spectrum anticancer activity of a novel heterocyclic compound 1 containing the title imidazo[4,5-e][1,3]diazepine ring system have been reported. The compound shows potent in vitro antitumor activity with low micromolar IC(50)'s against prostate, lung, breast, and ovarian cancer cell lines tested. The long alkyl chain attached to the six-position of the heterocyclic ring of 1 appears to be necessary for the observed biological activity.

The first synthesis of a novel 5:7:5-fused diimidazodiazepine ring system and some of its chemical properties.

The first synthesis of a novel 5:7:5-fused heterocyclic ring system, a diimidazodiazepine, is reported. The propensity of the ring system to undergo facile, acid-catalyzed nucleophilic addition reactions by neutral carbon and nitrogen nucleophiles has been explored. The ring system has potential future applications in mechanistic studies of formation and repair of DNA interstrand cross-links.

Inhibition of adenosine deaminase by analogues of adenosine and inosine, incorporating a common heterocyclic base, 4(7)-amino-6(5)H-imidazo[4,5-d]pyridazin-7(4)one.

Four nucleoside analogues ( 1- 4) containing a common heterocyclic base, 4(7)-amino-6(5) H-imidazo[4,5- d]pyridazin-7(4)one, were screened against calf-intestine adenosine deaminase. Compounds 1 and 3 with K(i) values of 10-12 microM are more than four times as potent inhibitors of ADA compared with 2 and 4, with K(i) values of 51-52 microM. Also, 3 is not a substrate of ADA.

An analogue of AICAR with dual inhibitory activity against WNV and HCV NTPase/helicase: synthesis and in vitro screening of 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1-beta-D-ribofuranoside.

The title compound (4) was synthesized by the reaction of ethyl 1-(2,3,5-tri-O-benzoyl-beta-d-ribofuranosyl)-5-formylimidazole-4-carboxylate with excess guanidine in ethanol at reflux. Compound 4 was evaluated in vitro against NTPases/helicases of four different viruses of the Flaviviridae family, including the West Nile virus (WNV), hepatitis C virus (HCV), dengue virus (DENV), and the Japanese encephalitis virus (JEV), employing both an RNA and a DNA substrate. The compound showed activity against NTPase/helicase of WNV and HCV with an IC(50) of 23 and 37 microM, respectively, when a DNA substrate was employed, while no activity was observed when an RNA substrate was used.

Design of inhibitors against guanase: synthesis and biochemical evaluation of analogues of azepinomycin.

As part of a program to design rational, mechanism-based inhibitors of guanase, we report here the synthesis and biochemical screening of two analogues of azepinomycin (1 and 2), a naturally occurring inhibitor of guanase, known to mimic the transition-state of the enzyme-catalyzed reaction. Our biochemical results show that compounds 1 and 2 are competitive inhibitors with K(i) of 2.01+/-0.

Nucleosides with self-complementary hydrogen-bonding motifs: synthesis and base-pairing studies of two nucleosides containing the imidazo[4,5-d]pyridazine ring system.

Synthesis and base-pairing studies of two 2'-deoxyribonucleosides, containing a common heterocyclic base, 7(4)-amino-5(6)H-imidazo[4,5-d]pyridazin-4(7)one (1 and 2), have been reported. The synthesis was accomplished by base-promoted deoxyribosylation of ethyl 5(4)-cyanoimidazole-4(5)-carboxylate (6), followed by ring-closure with hydrazine hydrate. The 1H NMR-based base-pair studies were conducted using DMF-d7 as a solvent by measuring changes in chemical shifts of the amino, hydrazide, imidazole H-2, and the sugar H-1' protons of the nucleosides with variations in concentrations and temperatures.

A novel imidazole nucleoside containing a diaminodihydro-S-triazine as a substituent: inhibitory activity against the West Nile virus NTPase/helicase.

The attempted synthesis of a ring-expanded guanosine (1) containing the imidazo[4,5-e][1,3]diazepine ring system by condensation of 1-(2'-deoxy-beta-D-erythropentofuranosyl)-4-ethoxycarbonylimidazole-5-carbaldehyde (2) with guanidine resulted in the formation of an unexpected product, 1-(2'-deoxy-beta-D-erythropentofuranosyl)-5-(2, 4-diamino-3, 6-dihydro-1,3, 5-triazin-6-yl)imidazole-4-carboxamide (7). The structure as well as the pathway of formation of 7 was corroborated by isolation of the intermediate, followed by its conversion to the product. Nucleoside 7 showed promising in vitro anti-helicase activity against the West Nile virus NTPase/helicase with an IC50 of 3-10 microg/mL.