Cytotoxic Alkylynols of the Sponge Cribrochalina vasculum : Structure, Synthetic Analogs and SAR Studies.

A series of twenty-three linear and branched chain mono acetylene lipids were isolated from the Caribbean Sea sponge Cribrochalina vasculum . Seventeen of the compounds, 1-17 , are new, while six, 18-23 , were previously characterized from the same sponge. Some of the new acetylene-3-hydroxy alkanes 1 , 6 , 7 , 8 , 10 were tested for selective cytotoxicity in non-small cell lung carcinoma (NSCLC) cells over WI-38 normal diploid lung fibroblasts. Compound 7 , presented clear tumor selective activity while, 1 and 8 , showed selectivity at lower doses and 6 and 10 , were not active towards NSCLC cells at all. The earlier reported selective cytotoxicity of some acetylene-3-hydroxy alkanes ( scal -18 and 23 ), in NSCLC cells and/or other tumor cell types were also confirmed for 19 , 20 and 22 . To further study the structure activity relationships (SAR) of this group of compounds, we synthesized several derivatives of acetylene-3-hydroxy alkanes, rac - 18 , scal-S - 18 , R - 18 , rac - 27 , rac - 32 , R - 32 , S - 32 , rac - 33 , rac - 41 , rac - 42 , rac - 43 , rac - 45 , rac - 48 and rac - 49 , along with other 3-substituted derivatives, rac - 35 , rac - 36 , rac - 37 , rac - 38 , rac - 39 and rac - 40 , and assessed their cytotoxic activity against NSCLC cells and diploid fibroblasts. SAR studies revealed that the alcohol moiety at position 3 and its absolute R configuration both were essential for the tumor cell line selective activity while for its cytotoxic magnitude the alkyl chain length and branching were of less significance.