THE INOPHYLLUMS, NOVEL INHIBITORS OF HIV-1 REVERSE-TRANSCRIPTASE ISOLATED FROM THE MALAYSIAN TREE, CALOPHYLLUM-INOPHYLLUM LINN

As part of a search for novel inhibitors of HIV-1 reverse transcriptas e, the acetone extract of the giant African snail, Achatina fulica, wa s shown to be active. Fractionation of the extract yielded inophyllums A, B, C, and E and calophyllolide (1a, 2a, 3a, 3b, and 6), previously isolated from Calophyllum inophyllum Linn., a known source of nutriti on for A. fulica. From a methanol/ methylene chloride extract of C. in ophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inop hyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum, A (1a) was determ ined to be 10(R), 11(S), 12(S) from a single-crystal X-ray analysis of its 4-bromobenzoate derivative, and the relative stereochemistries of the other inophyllums isolated from C. inophyllum were established by a comparison of their H-1 NMR NOE values and coupling constants to th ose of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HI V reverse transcriptase with IC50 values of 38 and 130 nM, respectivel y, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 mu M). Closely related inophyllums A, C, D, and E, including calo phyllic acids, were significantly less active or totally inactive, ind icating certain structural requirements in the chromanol ring. Altoget her, 11 compounds of the inophyllum class were isolated from C. inophy llum and are described together with the SAR of these novel anti-HIV c ompounds.