RECENT PROGRESS IN CALOPHYLLUM COUMARINS AS POTENT ANTI-HIV AGENTS - Medicinal Chemistry of Bioactive Natural Products - page 334

acts early in the infection process, similar to the NRTI such as zalcitabine. In
enzyme inhibition assays, calanolide A potently and selectively inhibited recombi-
nant HIV-1 RT but not cellular DNA polymerases or HIV-2 RT. In vitro antiviral
studies have indicated that protective activity of ( þ )-calanolide A against a wide
variety of HIV-1 isolates including synctium-inducing and non-synctium-inducing
viruses and both T-cell tropic and monocycle-macrophage tropic viruses. 36
Kinetic analysis demonstrated that ( þ )-calanolide A inhibited HIV-1 RT by a
complex mechanism involving two possible binding sites; one of the calanolide
binding sites is near both the pyrophosphate binding site and the active site of
the RT enzyme. 37,38
Evaluation of the safety and pharmacokinetics of a single dose of ( þ )-calanolide
A has been accomplished in 47 healthy HIV uninfected adult volunteers. Pharma-
cokinetic parameters were highly variable. The half-life (t 1/2 ) was about 21 hours in
those receiving an 800-mg dose, which suggests that ( þ )-calanolide A may be sui-
table for once-daily dosing. Both mean maximum plasma concentration (C max ) and
area under the concentration curve (AUC) values increased with the dose. However,
women seemed to have a higher plasma drug level and a longer elimination half-life
than men, because this difference may be caused by the differences in their body
weight. 36

8.3.2 Clinical Trial of ( þ )-Calanolide A

The clinical development of calanolide A commenced in 1997. According to the
phase IA clinical studies, it was indicated that ( þ )-calanolide A was safe and
well tolerated over a range of different single- and multiple-dose regimens in 94
healthy HIV uninfected adult volunteers. 39 A phase IB study to evaluate calanolide
A with different twice-a-day regimens for 14 days in 32 HIV-positive patients with
no previous antiretroviral therapy. The phase IB studies showed a trend in viral
reduction as the dosing was increased in AIDS patients. However, there was no
existence of the emergency of viral mutants over the period of study. 40,41 It was
possible to indicate that calanolide A could delay the onset of drug-resistant viral
strains. The most frequently reported clinical adverse events were nausea, dyspep-
sia, and headache. No rashes have been observed. Sarawake MediChem Pharma-
ceuticals Inc. plans to conduct a phase II/III trial in 2004.

8.4 PREPARATION OF CALOPHYLLUM COUMARINS

8.4.1 Total Synthesis of Racemic Calophyllum Coumarins

8.4.1.1 Total Synthesis of Racemic Calanolides
Chenara et al. 42 was the first research group to establish the racemic calanolide A
( 1) in 1993 (Scheme 8-1) and the related ( )-calanolide C and D via a five-step
synthesis with 15% overall yield starting from phlorglucinol and then constructed
the coumarin (A, B rings) followed by the chromanone ring (C) using a Lewis