The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn

Abstract

As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was 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 nutrition for A. fulica. From a methanol/methylene chloride extract of C. inophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inophyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum A (1a) was determined 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 1H NMR NOE values and coupling constants to those of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HIV reverse transcriptase with IC50 values of 38 and 130 nM, respectively, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 microM). Closely related inophyllums A, C, D, and E, including calophyllic acids, were significantly less active or totally inactive, indicating certain structural requirements in the chromanol ring. Altogether, 11 compounds of the inophyllum class were isolated from C. inophyllum and are described together with the SAR of these novel anti-HIV compounds.

Apoptosis inducing activity of 4-substituted coumarins from Calophyllum brasiliense in human leukaemia HL-60 cells

“…Since then, the chemical constituents of Calophyllum species have been actively studied (Patil et al 1993;Taylor et al 1994;Currens et al 1996;Zembower et al 1997;McKee et al 1998;Ishikawa 2000;Sekino et al 2004). Systematic studies of the chemical constituents of Calophyllum plants have been conducted by our group, and we showed that C. brasiliense Camb.…”

HIV-1 Inhibitory Compounds from Calophyllum brasiliense Leaves

“…The chemical analysis indicates that main compounds of C. brasiliense hexane extract from the leaves are two triterpenes, friedelin (1) and canophyllol (2), and three chromanone carboxylic acids, apetalic acid (3), isoapetalic acid (4) and a structural isomer of isoapetalic acid (5). The minority compounds are four dipyranocoumarins, (ϩ)-calanolide A (6), (Ϫ)-calanolide B (7), (ϩ)-calanolide C (8) and soulattrolide (9).…”

“…austrocoriaceum; 1) inophyllums B and P isolated from C. inophyllum; 2) soulattrolide isolated from C. inophyllum 3) and C. teysmanii.…”

HIV-1 Inhibition by Extracts of Clusiaceae Species from Mexico

“…9,10) Coumarins and benzophenones with these antiviral properties have been isolated from several plant species of the Clusiaceae family through bioguided fractionation. Among the most important coumarins able to inhibit HIV-1 RT with low cytotoxicity on uninfected cells are: (ϩ)-calanolide A, (Ϫ)-calanolide B, 11,12) (ϩ) inophyllum B and P, 13,14) soulattrolide; 15) (ϩ)-cordatolide A and (Ϫ)-cordatolide B.…”