Discovery and SAR of a series of 4,6-diamino-1,3,5-triazin-2-ol as novel non-nucleoside reverse transcriptase inhibitors of HIV-1.

The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat. A preliminary modeling study was conducted to understand the binding mode of this series of compounds.

The first examples of ring-closing olefin metathesis of vinyl chlorides.

[reaction: see text] Ring-closing metathesis (RCM) of olefinic vinyl chlorides can be effected by using the second generation Grubbs catalyst (10 mol %, PhH, 65 degrees C) to produce a variety of carbocyclic and heterocyclic five-, six-, and seven-membered rings in excellent yields.

Studies of intramolecular cyclizations of N-acyliminium ions derived from acyclic ketones: unanticipated stereochemical and structural results.

[reaction: see text] Intramolecular cyclizations of a series of (E)- and (Z)-olefinic acyclic ketone-derived N-acyliminium ions have been studied. It has been found that both the course of the reaction and the stereochemistry of the products are critically dependent upon the tether length and olefin geometry of the cyclization substrate.

Synthesis and pharmacological evaluation of N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a potent antimitotic agent.

The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.