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 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.
Patil
A D
AD
Department of Biomolecular Discovery, SmithKline Beecham Pharmaceuticals R & D, King of Prussia, Pennsylvania 19406.
Freyer
A J
AJ
Eggleston
D S
DS
Haltiwanger
R C
RC
Bean
M F
MF
Taylor
P B
PB
Caranfa
M J
MJ
Breen
A L
AL
Bartus
H R
HR
Johnson
R K
RK
D000107:Acetylation; D000818:Animals; D002839:Chromans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors; D012908:Snails / Q000737:chemistry; D013329:Structure-Activity Relationship; D014197:Trees
D002839:Chromans; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase