Chemistry Reference
In-Depth Information
Natural products have been and will be an important resource for new bioactive
compounds. (
þ
)-calanolide A (1) is the only natural product undergoing clinical
trial for AIDS patients. A combination of the (
þ
)-calanolide A and (
)-calanolide
B with a variety of mechanistically diverse HIV inhibitory drugs such as AZT, 3TC,
ddC, and ddI (NRTIs), nevirapin (NVP, NNRTI), indinavir (IDV), saquinavir
(SQV), ritonavir (RTV), and nefinavir (NFV), protease inhibitors exhibited either
additive or synergistic interactions. Furthermore, a combination of (
þ
)-calanolide
A with one NRTI and one PI yielded synergistic anti-HIV activity, whereas the com-
bination of the (
þ
)-calanolide A with one NRTI and one NNRTI showed an additive
effect.
29
(
þ
)-calanolide A, (
)-calanolide B (costatolide), and dihydrocostatolide
were evaluated in different cell lines (CEM-SS, H9, MT2, AA5, V937, etc.)
infected with both laboratory-derived and clinical strains of HIV-1, HIV-2, and
SIV.
30
The anti-HIV-1 activity (EC
50
) of these compounds ranged from 0.08 to
0.5, 0.06 to 1.4, and 0.1 to 8.8 mM for (
þ
)-calanolide A, (
)-calanolide B, and
dihydrocostatolide, respectively. However, no compound exhibited activity against
HIV-2 or SIV. Furthermore, calanolides were active against a wide range of HIV-
strains in various cell lines. The three calanolide stereoisomers showed their anti-
viral activities for resistance to a variety of NNRTIs as shown in Table 8-3.
The calanolides were active against viral isolates with the Y181C amino acid
mutation in the HIV-1 RT, which is a commonly observed mutation in both labora-
tory and clinical viral isolates, and it was associated with high-level resistance to
most other NNRTIs, such as nevirapine, pyridinone, E-BPTU, UC38, and diphenyl-
sulfone. All tested calanolides exhibited no antiviral activity against NNRTI-related
mutations, L100I, K103N, and Y188H. A unique and important feature of calano-
lides distinguishes it from the current marketed and developmental NNRTI. Addi-
tionally, (
þ
)-calanolide A possessed anti-Mycobacterium tuberculosis (TB).
31
No
anti-HIV agent, either in development or approved by the FDA, that exhibits this
therapeutic capability. However, AIDS patients are more susceptible to TB com-
pared with the healthy people. It makes (
þ
)-calanolide A a valuable therapeutic
agent to AIDS patients. A preclinical program of antituberculosis properties of
(
þ
)-calanolide A has been investigated by Sarawake MediChem Pharmaceuticals.
8.2.1.2 Anti-HIV-1 Activity of Calanolides in Hollow Fiber Mouse
Evaluation of (
þ
)-calanolide A (1) in a hollow fiber culture-based in a SCID mouse
assay of antiviral efficacy indicated that (
þ
)-calanolide A exhibited significant anti-
HIV-1 activity after oral or parenteral administration on a once-daily (200 mg/kg/
dose) or twice-daily (150 mg/kg/dose) treatment. Furthermore, a synergistic effect
was observed in the combination of (
þ
)-calanolide A and AZT.
32
8.2.2
Anti-HIV-1 Activity of Inophyllums
An inophyllum series was isolated from the Malaysia tree, Calophyllum inophyllum
Linn (bioassay-guided procedure) (
þ
)-inophyllum B (3), P (4), C (11), E (12), A
(17), D (18), inophyllum G-1 (19), G-2 (20), calophyllic acid (28), and isocalophyl-
lic acid (29). The (
þ
)-inophyllum P (4), an enantiomer of soulattrolide (16) and as
Search WWH ::
Custom Search