ABSTRACT
Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SAR analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (l)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.
Subject(s)
Benzophenones/chemical synthesis , Prodrugs/chemical synthesis , Tubulin Modulators/chemical synthesis , Valine/analogs & derivatives , Animals , Benzophenones/chemistry , Benzophenones/pharmacology , Cell Line, Tumor , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Nude , Neoplasm Transplantation , Prodrugs/chemistry , Prodrugs/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacologyABSTRACT
Polyunsaturated fatty acid-derived monoglycerides were characterized from the marine brown alga Sargassum sagamianum, collected from Jeju Island, Korea. A new compound of this structural class was isolated and determined to be 1-octadecatetraenoyl glycerol, by combined spectroscopic methods. Based on the structures and bioactivity of these compounds, a series of monoglycerides were synthesized using glycerol and various fatty acids. Several compounds exhibited moderate to significant inhibition of phospholipase A(2) and cyclooxygenase-2.
Subject(s)
Cyclooxygenase 2/drug effects , Monoglycerides/pharmacology , Phospholipase A2 Inhibitors , Sargassum/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Fatty Acids, Unsaturated/chemistry , Korea , Molecular Structure , Monoglycerides/chemical synthesis , Monoglycerides/isolation & purification , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The first syntheses of polyyne-containing sphingoid base analogues were achieved by employing our iterative strategy that uses a two-step acetylene homologation sequence. In this process, a bromoalkyne is homologated by one acetylene unit through a Pd-catalyzed cross-coupling with a TIPS-protected acetylene and a subsequent in situ AgF-mediated desilylative bromination. Repeating this homologation sequence followed by cross-coupling with the long-chained terminal acetylene provides access to the polyyne framework in good overall yields.
