Calanolide A

Scientific Name(s):Originally isolated from species Calophyllum lanigerum var. austrocoriaceum

Common Name(s): Calanolide A

Uses

Initial studies show promise for treating HIV-1.

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Dosing

Calanolide A is an investigational anti-HIV drug that has been given in early clinical trials at an oral dose of 200 to 800 mg; however, it is not available for use. Its safety and efficacy remain to be defined. 1

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Because this product is a relatively new discovery, no data are available.

Toxicology

Calanolide A is an investigational anti-HIV drug. Its safety and efficacy remain to be defined. 1

Botany

Calanolide A is a compound isolated from the latex of the tree, Calophyllum lanigerum var. austrocoriaceum , that grows in the rain forest of the Malaysian state of Sarawak on the island of Borneo. There are at least 200 species in the genus Calophyllum . 2 , 3

History

Rain forests are a very promising source of natural medicines because of their vast diversity. It has been estimated that more than half of the world's 250,000 plant species exist in tropical rain forests. Searching for natural drugs in these areas, the National Cancer Institute (NCI) contracts scientists to gather specimens for analysis. In 1987, an Illinois team obtained samples from many trees, one of which was Calophyllum lanigerum . Four years later, the NCI discovered that a preparation from this gum tree was very effective against the human immunodeficiency virus type 1 (HIV-1). 2 , 4 Confirmation of species was performed by comparison to Arnold Arboretum species and samples from the Singapore Botanic Garden. 4

Chemistry

Plants from the genus Calophyllum have been shown to contain xanthones, steroids, triterpenes, coumarins, and benzopyrans. Calanolide A falls into the category of a dipyranocoumarin. 3 It is classified as a nonnucleoside HIV-1 specific reverse transcriptase (RT) inhibitor. 3 , 5 Many studies in this area discuss findings from the genus Calophyllum , and offer structural representations, related compounds and their derivatives, modifications of the molecule, etc. 3 , 5 , 6 , 7 8 , 9 , 10 Calanolide A has been synthesized in the lab and was found to have similar actions to the natural product. 11

Uses and Pharmacology

HIV

This recently discovered natural product has been found to specifically inhibit the DNA polymerase activity of HIV-1 RT, but not HIV-2 RT. 12 This information warrants further investigation in human clinical trials. Calanolide A has been found to inhibit a wide variety of HIV-1 strains, drug-resistant strains, and HIV disease in various stages. Calanolide A appears to act early in the infection process similar to dideoxycytidine. 13 Calanolide A's complex biochemical mechanism of inhibition has suggested the presence of 2 binding sites, 1 competitive, 1 noncompetitive. Calanolide A binds near the active site of the enzyme and interferes with deoxynucleotide triphosphate binding. 14 Many RT inhibitors bind to a common site on HIV-1 RT; whereas calanolide A may bind to a different site or sites on the enzyme. 15 Changes in the nonnucleoside inhibitor binding site itself may also alter effects. One report discusses cross-resistance of certain viral strains. Single mutations at certain amino acids can yield virus with either higher or lower resistance. 16

Other related compounds from the genus Calophyllum possess HIV-inhibitory actions. Examples include costatolide, 17 , 18 dihydrocalanolide, 18 and certain cordatolides. 19 Calanolides, their derivatives and/or structural analogs from C. lanigerum and other Calophyllum species, and their anti-HIV activities have been reported. 6 , 7 , 8 , 9 , 10 , 20 , 21 HIV RT inhibitors of natural origin, including calanolide A, have been reviewed. 22

Animal data

In vivo, calanolide A has suppressed (HIV) viral replication in both IP and SC compartments in the hollow fiber mouse model. When combined with zidovudine, calanolide A had a synergistic effect. 23

Clinical data

As calanolide A is an investigational drug. No clinical data is available yet.

Dosage

Calanolide A is an investigational anti-HIV drug that has been given in early clinical trials at an oral dose of 200 to 800 mg; however, it is not available for use. Its safety and efficacy remain to be defined. 1

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Because this product is a relatively new discovery, no data are available.

Toxicology

It has been mentioned that substance from C. lanigerum destroys the HIV virus without killing healthy cells, 1 but toxicology information is limited because of its recent discovery.

Bibliography

1. Creagh T, Ruckle JL, Tolbert DT, et al. Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects. Antimicrob Agents Chemother . 2001;45:1379-1386.
2. Shenon P. Hunt in forests of Borneo aims to track down natural drugs. New York Times . 1994 Dec 6.
3. McKee T, et al. Pyranocoumarins from tropical species of the genus Calophyllum : A chemotaxonomic study of extracts in the National Cancer Institute Collection. J Nat Prod . 1998;61:1252-56.
4. Anonymous. Arnold Arboretum launches $8.2M capital campaign. The Harvard University Gazette . 1996 Jul 3.
5. McKee T, et al. New pyranocoumarins isolated from Calophyllum lanigerum and Calophyllum teysmannii . J Nat Prod . 1996;59:754–58.
6. Kashman Y, et al. The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum . J Med Chem . 1992;35(15):2735-43.
7. Galinis D, et al. Structure-activity modifications of the HIV-1 inhibitors (+)- calanolide A and (-)-calanolide B. J Med Chem . 1996;39(22):4507-10.
8. Boyd M, et al. Extraction of calanolide antiviral compounds from Calophyllum . US Pat Appl 1993 #Pat-appl-7-861 249, 1993.
9. Boyd M, et al. Calanolide and related antiretroviral compounds isolated from Calophyllum . 30 pp cont-in-part of US Patent Ser No. 861, 249, 1997.
10. Zembower D, et al. Structural analogues of the calanolide anti-HIV agents. Modification of the trans-10,11-dimethyldihydropyran-12-0l ring (ring C). J Med Chem . 1997;40(6):1005-17.
11. Flavin M, et al. Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers. J Med Chem . 1996;39(6):1303-13.
12. Hizi A, et al. Specific inhibition of the reverse transcriptase of human immunodeficiency virus type 1 and the chimeric enzymes of human immunodeficiency virus type 1 and type 2 by nonnucleoside inhibitors. Antimicrob Agents Chemother . 1993;37(5):1037-42.
13. Currens M, et al. Antiviral activity and mechanism of action of calanolide A against the human immunodeficiency virus type-1. J Pharmacol Exp Ther . 1996;279(2):645-51.
14. Currens M, et al. Kinetic analysis of inhibition of human immunodeficiency virus type-1 reverse transcriptase by calanolide A. J Pharmacol Exp Ther . 1996;279(2):652-61.
15. Boyer P, et al. Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase. J Virol . 1993;67(4):2412-20.
16. Buckheit R Jr, et al. Resistance to 1\N\[(2\Nhydroxyethoxy) methyl]-6-(phenylthio) thymine derivatives is generated by mutations at multiple sites in the HIV-1 reverse transcriptase. Virology . 1995;210(1):186-93.
17. Fuller R, et al. HIV-inhibitory natural products. 16. HIV-inhibitory coumarins from latex of the tropical rain forest tree Calophyllum teysmannii var. inophylloide. Bioorg Med Chem Lett . 1994;4(16):1961-64.
18. Buckheit R Jr, et al. Unique anti-human immunodeficiency virus activities of the nonnucleoside reverse transcriptase inhibitors calanolide A, costatolide, and dihydrocostatolide. Antimicrob Agents Chemother . 1999;43(8):1827-34.
19. Dharmaratne H, et al. Inhibition of human immunodeficiency virus type 1 reverse transcriptase activity by cordatolides isolated from Calophyllum cordato-oblongum . Planta Med . 1998;64(5):460-61.
20. Xu Z, et al. In vitro anti-human immunodeficiency virus (HIV) activity of the chromanone derivative, 12-oxocalanolide A, a novel NNRTI. Bioorg Med Chem Lett . 1998;8(16):2179-84.
21. Newman R, et al. Pharmaceutical properties of related calanolide compounds with activity against human immunodeficiency virus. J Pharm Sci . 1998;87(9):1077-80.
22. Matthee G, et al. HIV reverse transcriptase inhibitors of natural origin. Planta Med . 1999;65(6):493-506.
23. Xu Z, et al. In vivo anti-HIV activity of (+)-calanolide A in the hollow fiber mouse model. Bioorg Med Chem Lett . 1999;9(2):133-38.

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