ABSTRACT
A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Head and Neck Neoplasms/drug therapy , Indoles/chemistry , Indoles/therapeutic use , Tubulin Modulators/chemistry , Tubulin Modulators/therapeutic use , Animals , Antineoplastic Agents/pharmacokinetics , Caco-2 Cells , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Heterografts , Humans , Indoles/pharmacokinetics , Male , Mice , Mice, Nude , Microtubules/drug effects , Microtubules/metabolism , Microtubules/pathology , Neoplasm Transplantation , Structure-Activity Relationship , Tubulin/metabolism , Tubulin/ultrastructure , Tubulin Modulators/pharmacokineticsABSTRACT
During malaria surveys in Myanmar, 2 peculiar forms of Plasmodium malariae-like parasites were found. The morphologies of their early trophozoite stages were distinct from that of the typical P. malariae, resembling instead that of Plasmodium vivax, var. minuta, reported by Emin, and Plasmodium tenue, reported by Stephens, both in 1914. Two polymerase chain reaction (PCR)-based diagnoses, which target the same regions in the small subunit ribosomal RNA (SSUrRNA) genes, indicated that these parasites were new variant forms of P. malariae and that they could be separated into 2 genetic types that correlated with the 2 morphological types. Sequence analysis of the SSUrRNA and the circumsporozoite protein genes revealed that they were distinct both from each other and from other known P. malariae isolates and that the P. tenue-like type was closer to a monkey quartan malaria parasite, Plasmodium brasilianum. These results illustrate that the microscopic appearance of human P. malariae parasites may be more varied than previously assumed and suggest the value of molecular tools in the evaluation of malaria morphological variants.
