Calanolide A

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Calanolide A
Calanolide A.svg
Clinical data
ATC code
  • none
Pharmacokinetic data
Protein binding >97%
Metabolism Hepatic (mostly CYP3A4-mediated)
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C22H26O5
Molar mass 370.44 g/mol
3D model (JSmol)

Calanolide A is an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI). This compound was extracted from the Calophyllum lanigerum, of variety austrocoriaceum, trees in Lundu, Malaysian state of Sarawak in 1992 by United States National Cancer Institute (NCI). Due to rarity of the raw materials and low yield of the active ingredient, total synthesis of the compound was devised in 1996. For the same reason, its sister compound (-)-Calanolide B (also known as Costatolide) have been tauted as replacement. As a result of the discovery of Calanolide A, Sarawak Medichem pharmaceuticals company was established as a joint venture between US-based MediChem Research Inc and Sarawak state government. In 2006, Craun Research, a company established by Sarawak government, acquired Sarawak MediChem. In 2016, Craun Research announced the completion of Phase I clinical trials for Calanolide A.

History[edit]

In December 1986, Arnold Arboretum of the Harvard University in Massachusetts, requested permission from Sarawak state government to collaborate with Sarawak forest department to collect plants from Sarawak for phytochemical analysis. Permission was granted in May 1987.[1] The plants collection project was part of the many expeditions launched by United States National Cancer Institute (NCI), to find new natural substances to treat cancer and AIDS infection. In September 1987, a botanist named John Burley went on a mission to collect plant samples from a swamp forest at Lundu, Sarawak, Malaysia. He and his team routinely collected a kilogram of fruits, leaves, and twigs from each type of plant they encountered. Part of the samples were sent to NCI for analysis and the other part was sent to Harvard University Herbaria for safekeeping for future research. A sample which was labelled "Burley-and-Lee-351" although showing no effect when tested against cancer cells in cultures, was able to stop viral replication when tested against HIV-1 virus. The sample was later determined to have come from a tree identified as Calophyllum lanigerum[2] (locally known as Bintangor tree)[1] of variety austrocoriaceum.[2] Sarawak Forest Department was informed of the result in late 1991.[1]

On return trip to Sarawak in March 1992,[1] it was found that the tree had been cut down by local people most likely for fuel and building material. There was no other trees of the same variety existed in the Lundu region. The collectors then returned home with samples from other varieties of the Calophyllum lanigerum species, most of which failed to show any anti-HIV properties. Then, a few existing species were eventually located in the Singapore Botanic Gardens. With sufficient raw materials, the scientists were able to isolate the active ingredient as (+)-Calanolide A.[2] Since the plant source is relatively rare, a method of total synthesis was developed in 1996 which showed same effectiveness against HIV virus when compared to the original compound.[3] In addition, the samples collected from the trip in March 1992 yielded another positive result. A sister compound (-)-Calanolide B (also known as Costatolide) was isolated from the latex of Calophyllum teysmannii var. innophylloide trees. Sarawak Forestry Department was in collaboration with University of Illinois at Chicago (UIC) for sustainable harvest of (-)-Calanolide B.[4][5] Although Costatolide is less potent than Calanolide A, the yield from raw materials is much higher (20 to 25%) when compared to Calanolide A (0.05%). Therefore, Costatolide had been accepted as replacement for Calanolide A.[1] In June 1993, The Calophyllum Species (Prohibition of Felling and Restriction of Export) Order was issued by the Sarawak state government to ensure adequate supply of the trees for medicinal purposes.[1][6] In the same year, International Convention on Biological Diversity (CBD) treaty came into effect with 179 countries as its signatories. However, the United States did not sign the treaty. Therefore, the Sarawak state government set up Sarawak Biodiversity Centre (SBC) in 1997 to regulate bioprospecting activities in the state.[7][8] Craun Research Sdn Bhd was also established by the Sarawak state government in 1993.[9]

In 1994, NCI signed a "letter of collection" with Sarawak state government. NCI also partnered with MediChem Research Inc based in Lemont, Illinois to develop the Calanolide compound. In 1995, NCI granted MediChem all rights to develop the compound. In 1996, Medichem entered a joint venture with Sarawak state government where the former provided technical expertise and facilities for Sarawak scientists. Meanwhile, the state government provided further funding for the development of the compound. Sarawak MediChem pharmaceuticals company was then created as a result of the joint venture. Both partners have 50:50 percent stake in all intellectual property rights of the venture.[4]

In December 2006, Craun Research acquired Sarawak MediChem Pharmaceuticals.[10] In 2016, Craun Research announced the successful completion of Phase I trial of the drug. Following this, they will conduct a market survey of this product and out-licensing the product to other pharmacology companies.[11]

Mechanism of action[edit]

Calanolide A is unique among non-nucleoside reverse transcriptase inhibitor (NNRTIs) in that it may bind two distinct sites in reverse transcriptase, namely active site and Foscarnet binding site of the enzyme. The drug also acts in synergistic fashion with nevirapine in inhibiting HIV-1 virus.[12]

Side effects[edit]

Calanolide A has a relatively good safety profile. A Phase I clinical trial done in 2001 on 47 healthy subjects showed that the side effects were taste alteration, headache, belching, and nausea.[13]

References[edit]

  1. ^ a b c d e f "The Calophyllum story". Sarawak Forest Department. Archived from the original on 27 May 2018. Retrieved 27 May 2018.
  2. ^ a b c Edward O, Wilson (2002). "What Is Nature Worth?". Wilson Quarterly. 26 (1): 36–37. JSTOR 40260568.
  3. ^ Flavin MT, Rizzo JD, Khilevich A, et al. (1996). "Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+)-Calanolide A and its enantiomers". J Med Chem. 39 (6): 1303–13. doi:10.1021/jm950797i. PMID 8632437.
  4. ^ a b Kerry Ten, Kate; Adrian, Wells. Benefit-sharing case study - The access and benefit-sharing policies of the United States National Cancer Institute: a comparative account of the discovery and development of the drugs Calanolide and Topotecan (PDF). Convention of Biological Diversity. pp. 3–5. Archived from the original (PDF) on 8 December 2017. Retrieved 27 May 2018.
  5. ^ Richard W, Fuller; Heidi R, Bokesch; Kirk R, Gustafson; Tawnya C, McKee (25 August 1994). "HIV-inhibitory coumarins from latex of the tropical rainforest tree Calophyllum teysmannii var. inophylloide". Bioorganic & Medicinal Chemistry Letters. 4 (16): 1961–1964. doi:10.1016/S0960-894X(01)80543-6.
  6. ^ Philip, Shenon (6 December 1994). "Hunt in Forests of Borneo Aims to Track Down Natural Drugs". New York Times. Archived from the original on 27 May 2018. Retrieved 27 May 2018. For its part, the provincial government of Sarawak, the Malaysian state where the Calophyllum trees were found, has banned logging of the species, a critical step given how much of the rain forests of Sarawak have already been ravaged by the timber industry.
  7. ^ Richard Lyold, Parry (1 August 2001). "Bio-pirates raid trees in the swamps of Borneo". The Independent (UK). Archived from the original on 27 May 2018. Retrieved 27 May 2018.
  8. ^ "About Sarawak Biodiversity Centre – Profile". Sarawak Biodiversity Centre. Archived from the original on 6 December 2014. Retrieved 16 November 2015.
  9. ^ "Message From Our CEO". Craun Research Sdn Bhd. Archived from the original on 31 July 2017. Retrieved 27 May 2018.
  10. ^ "Company Overview of Sarawak MediChem Pharmaceuticals Inc". Bloomberg. Archived from the original on 27 May 2018. Retrieved 27 May 2018.
  11. ^ "New milestone for anti-HIV drug". The Star (Malaysia). 26 November 2016. Archived from the original on 25 May 2018. Retrieved 25 May 2018.
  12. ^ Currens MJ, Mariner JM, McMahon JB, Boyd MR (1996). "Kinetic analysis of inhibition of human immunodeficiency virus type-1 reverse transcriptase by calanolide A". J Pharmacol Exp Ther. 279 (2): 652–61. PMID 8930168.
  13. ^ Terri, Creagh; John L, Ruckle; Dwain T, Tolbert; Jeremy, Giltner (May 2001). "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". Antimicrobial Agents and Chemotherapy. American Society for microbiology. 45 (5): 1379–1386. doi:10.1128/AAC.45.5.1379-1386.2001. PMC 90477. Taken together, the above data demonstrate that the favorable safety profile, ...