Preparation and cytotoxicity evaluation of acetylated fijianolides (A.K.A. laulimalide).
Cook CV, Johnson TA, Coppage D, McIntosh NL, Ogarrio MA, Tenney K, Valeriote FA, and Crews P. Preparation and cytotoxicity evaluation of acetylated fijianolides (A.K.A. laulimalide). FASEB Journal 2018; 32(1)
The fijianolides (a.k.a. laulimalides) discovered in the 1980s at UC Santa Cruz and U. Hawaii continue to attract attention as a unique class of sponge-derived polyketides. They've shown low nanomolar cytotoxicity against human tumor cell lines. A mechanism for this activity is their ability to stabilize microtubles at a similar but distinct site to that of the anti-cancer drug Taxol®. Fijianolide B (2, aka laulimalide), which is extremely bioactive was the subject of two in vivo studies by different labs and resulted in different outcomes. One study reported significant inhibition of growth of solid tumors over 28 days without toxicity.1 While another reported minimal inhibition of solid tumor growth accompanied by significant toxicity.2 We have launched a new campaign to re-examine this dichotomy and create a more stable pre-clinical candidate, because 2 rearranges over time to the much less active 1. In this poster we describe the previous structure activity relationship (SAR) data of 2, updated pharmacokinetic data, preparation of diacetylated analogs, and their relative bioactivites against pancreatic and human colon tumor cell lines.
Domchek SM, Postel-Vinay S, Bang YJ, Park YH, Alexandre J, Delord JP, Italiano A, You B, Bastian S, Krebs M, Wang D, Waqar S, Angell H, Learoyd M, Chang SC, Gresty C, Herbolsheimer P, and Kaufman B. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). Cancer Res 2018; 78(4):1.