ABSTRACT
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.
Subject(s)
Indoles/chemical synthesis , Isonicotinic Acids/chemical synthesis , Sulfonamides/chemical synthesis , Tubulin Modulators/chemical synthesis , Animals , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colchicine/chemistry , Drug Screening Assays, Antitumor , G2 Phase , Humans , Indoles/chemistry , Indoles/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Tubulin/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
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.
Subject(s)
Drug Discovery , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Triazines/chemical synthesis , Triazines/pharmacology , Animals , Models, Molecular , Rats , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of substituted biphenyl ethylene ether compounds has been designed to target the gp41N-trimer in order to inhibit formation of the six-helical bundle that represents the end state of gp41-mediated viral fusion. A size exclusion HPLC based helical bundle formation (HBF) assay was developed to evaluate in vitro inhibitory affinity of the inhibitors. The most potent compound 1 had an IC(50) of 31microM. The binding of compound 1 to the proposed hydrophobic pocket of gp41 was further validated by site-directed peptide mutagenesis experiments.
