HIV inhibitory natural products. Part 7. The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum

Abstract

Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1 microM and 0.4 microM, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

“…X-Gal (5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside) was also purchased from Sigma. Polymerase assays utilized the reagents poly(rAdT) [12][13][14][15][16][17][18] , poly(rC-dG) [12][13][14][15][16][17][18] , and poly(dT-dA) [12][13][14][15][16][17][18] (Pharmacia LKB, Piscataway, N.J.) and 16S-23S rRNA (Boehringer Mannheim, Indianapolis, Ind.) and random nonamer primers (Synthetic Genetics, San Diego, Calif.).…”

“…The preparation, enzymatic activities, and drug sensitivities of these two variant RTs have been previously described (5, 6). The three template-primer systems used to evaluate the inhibition of the various RT preparations by michellamine B consisted of poly(rA-dT) [12][13][14][15][16][17][18] , poly(rC-dG) [12][13][14][15][16][17][18] , and rRNA-primer. Recombinantderived DNA polymerases ␣ and ␤ were the kind gift of Sam Wilson (University of Texas Medical Branch, Center for Molecular Sciences).…”

Inhibition of reverse transcriptase of human immunodeficiency virus type 1 and chimeric enzymes of human immunodeficiency viruses types 1 and 2 by two novel non‐nucleoside inhibitors

“…More recently, the calanolides have been identified as a second type of non-nucleoside inhibitors of HIV-1 RT (NNRTI). Hence, a TIBO-and nevirapineresistant mutant strain of HIV-1 was found to be inhibited by calanolide A [8].…”

Identification of anti-HIV and anti-Reverse Transcriptase activity from Tetracera scandens

“…An alternative effort to solve these problems has also been to actively seek novel antiviral agents from various natural sources such as traditionally used medicinal herbs and plants (10). Some examples include betulinic acid from Syzygium claviflorum (11,12), various calanolides from Calophyllum langerium (13,14), and geraniin from Phyllanthus amarus (15).…”