The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum.
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.
Kashman
Y
Y
Laboratory of Drug Discovery Research and Development, Frederick Cancer Research and Development Center (NCI-FCRDC), Maryland 21702-1201.
Gustafson
K R
KR
Fuller
R W
RW
Cardellina
J H
JH
McMahon
J B
JB
Currens
M J
MJ
Buckheit
R W
RW
Hughes
S H
SH
Cragg
G M
GM
Boyd
M R
MR
D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002853:Chromatography, Liquid; D003374:Coumarins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014197:Trees / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003374:Coumarins; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors; C075958:calanolide B; D054303:HIV Reverse Transcriptase; C075959:calanolide A