Calanolide A

Identification

Generic Name

Calanolide A

DrugBank Accession Number

DB04886

Background

Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals. A preliminary dosing study among HIV-infected individuals showed a significant antiviral effect compared with placebo.

Type

Small Molecule

Groups

Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Calanolide A (DB04886)

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Weight

Average: 370.4388
Monoisotopic: 370.178023942

Chemical Formula

C₂₂H₂₆O₅

Synonyms

• (+)-calanolide A

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Pharmacology

Indication

For use in combination treatment of HIV infection (AIDS).

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals. The drug is metabolised by cytochrome P450 CYP3A, and its developers have suggested that drug levels may be enhanced if co-administered with ritonavir (Norvir). The drug is active in the test tube against HIV with the two most common NNRTI-related mutations, K103N and Y181C, and selects for a mutation which does not cause cross-resistance with any other NNRTIs currently under investigation. A substitution at codon Y188H of reverse transcriptase has been associated with 30-fold resistance to calanolide A in vitro (Quan 1999). The compound is essentially inactive against strains of the less common HIV type 2.

Mechanism of action

Viral life-cycle studies indicate that calanolide A acts early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibits recombinant HIV type 1 RT but not cellular DNA polymerases or HIV type 2 RT within the concentration range tested.

Target	Actions	Organism
UGag-Pol polyprotein	Not Available	HIV-1

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic.

Route of elimination

Not Available

Half-life

20 hours for 800mg

Clearance

Not Available

Adverse Effects

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Toxicity

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Acetohexamide	The therapeutic efficacy of Acetohexamide can be increased when used in combination with Calanolide A.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Calanolide A.
Anthrax vaccine	The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Calanolide A.
Bacillus calmette-guerin substrain connaught live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Calanolide A.
Bacillus calmette-guerin substrain russian BCG-I live antigen	The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Calanolide A.

Food Interactions

Not Available

Categories

Drug Categories

• Anti-HIV Agents
• Anti-Infective Agents
• Anti-Retroviral Agents
• Antiviral Agents
• Benzopyrans
• Calophyllum
• Coumarins
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Heterocyclic Compounds, Fused-Ring
• Plant Extracts
• Pyrans

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as angular pyranocoumarins. These are organic compounds containing a pyran (or a hydrogenated derivative) angularly fused to a coumarin moiety.

Kingdom

Organic compounds

Super Class

Phenylpropanoids and polyketides

Class

Coumarins and derivatives

Sub Class

Pyranocoumarins

Direct Parent

Angular pyranocoumarins

Alternative Parents

Pyranochromenes / 2,2-dimethyl-1-benzopyrans / Pyranones and derivatives / Alkyl aryl ethers / Benzenoids / Heteroaromatic compounds / Secondary alcohols / Lactones / Oxacyclic compounds / Organic oxides / Hydrocarbon derivatives

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Substituents

1-benzopyran / 2,2-dimethyl-1-benzopyran / Alcohol / Alkyl aryl ether / Angular pyranocoumarin / Aromatic heteropolycyclic compound / Benzenoid / Benzopyran / Chromane / Ether / Heteroaromatic compound / Hydrocarbon derivative / Lactone / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organooxygen compound / Oxacycle / Pyran / Pyranochromene / Pyranone / Secondary alcohol

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

organic heterotetracyclic compound, secondary alcohol, delta-lactone, cyclic ether (CHEBI:65552) / coumarins (C09147)

Affected organisms

• Human Immunodeficiency Virus

Chemical Identifiers

UNII

S5A9TQN46W

CAS number

142632-32-4

InChI Key

NIDRYBLTWYFCFV-FMTVUPSXSA-N

InChI

InChI=1S/C22H26O5/c1-6-7-13-10-15(23)26-21-16(13)20-14(8-9-22(4,5)27-20)19-17(21)18(24)11(2)12(3)25-19/h8-12,18,24H,6-7H2,1-5H3/t11-,12-,18+/m1/s1

IUPAC Name

(10R,11S,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-6,10,11,12-tetrahydro-2H-1,5,9-trioxatriphenylen-2-one

SMILES

CCCC1=CC(=O)OC2=C1C1=C(C=CC(C)(C)O1)C1=C2[C@@H](O)[C@H](C)[C@@H](C)O1

References

General References

1. Eiznhamer DA, Creagh T, Ruckle JL, Tolbert DT, Giltner J, Dutta B, Flavin MT, Jenta T, Xu ZQ: Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers. HIV Clin Trials. 2002 Nov-Dec;3(6):435-50. [Article]
2. Xu ZQ, Barrow WW, Suling WJ, Westbrook L, Barrow E, Lin YM, Flavin MT: Anti-HIV natural product (+)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. Bioorg Med Chem. 2004 Mar 1;12(5):1199-207. [Article]
3. Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T: Concise synthesis of anti-HIV-1 active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-Michael addition. J Org Chem. 2004 Apr 16;69(8):2760-7. [Article]

External Links

KEGG Compound

C09147

PubChem Compound

64972

PubChem Substance

175426889

ChemSpider

58497

BindingDB

50002662

ChEBI

65552

ChEMBL

CHEMBL267447

ZINC

ZINC000001645454

Wikipedia

Calanolide_A

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
1	Completed	Treatment	Human Immunodeficiency Virus (HIV) Infections	1
1	Unknown Status	Treatment	Human Immunodeficiency Virus (HIV) Infections	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0178 mg/mL	ALOGPS
logP	4.18	ALOGPS
logP	3.79	Chemaxon
logS	-4.3	ALOGPS
pKa (Strongest Acidic)	13.63	Chemaxon
pKa (Strongest Basic)	-3.4	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	64.99 Å2	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	104.11 m3·mol-1	Chemaxon
Polarizability	41 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9901
Blood Brain Barrier	+	0.8789
Caco-2 permeable	+	0.7886
P-glycoprotein substrate	Substrate	0.6977
P-glycoprotein inhibitor I	Non-inhibitor	0.5696
P-glycoprotein inhibitor II	Non-inhibitor	0.521
Renal organic cation transporter	Non-inhibitor	0.9172
CYP450 2C9 substrate	Non-substrate	0.7451
CYP450 2D6 substrate	Non-substrate	0.847
CYP450 3A4 substrate	Substrate	0.5905
CYP450 1A2 substrate	Non-inhibitor	0.7102
CYP450 2C9 inhibitor	Inhibitor	0.5
CYP450 2D6 inhibitor	Non-inhibitor	0.8947
CYP450 2C19 inhibitor	Non-inhibitor	0.7118
CYP450 3A4 inhibitor	Non-inhibitor	0.7872
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.7001
Ames test	Non AMES toxic	0.6246
Carcinogenicity	Non-carcinogens	0.9035
Biodegradation	Not ready biodegradable	0.9889
Rat acute toxicity	2.7417 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9428
hERG inhibition (predictor II)	Non-inhibitor	0.9579

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-0009000000-752ed0e113942e91aa8c
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-014i-0009000000-a67d1ed90ddad2c3b6c2
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-016r-0009000000-9569316b8ddae1be718e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-0009000000-6c0ec9baa0cb9f105986
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0fb9-0029000000-08d7835259bdf95747ce
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0ufs-0039000000-acabfb48a83f244af657
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	202.5620567	predicted	DarkChem Lite v0.1.0
[M-H]-	191.53519	predicted	DeepCCS 1.0 (2019)
[M+H]+	202.5810567	predicted	DarkChem Lite v0.1.0
[M+H]+	193.93074	predicted	DeepCCS 1.0 (2019)
[M+Na]+	202.8410567	predicted	DarkChem Lite v0.1.0
[M+Na]+	199.99294	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Gag-Pol polyprotein

Kind

Protein

Organism

HIV-1

Pharmacological action

Unknown

General Function

Zinc ion binding

Specific Function

Gag-Pol polyprotein: Mediates, with Gag polyrotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spher...

Gene Name

gag-pol

Uniprot ID

P03369

Uniprot Name

Gag-Pol polyprotein

Molecular Weight

162014.15 Da

References

1. Hanna L: Calanolide A: a natural non-nucleoside reverse transcriptase inhibitor. BETA. 1999 Apr;12(2):8-9. [Article]
2. Eiznhamer DA, Creagh T, Ruckle JL, Tolbert DT, Giltner J, Dutta B, Flavin MT, Jenta T, Xu ZQ: Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers. HIV Clin Trials. 2002 Nov-Dec;3(6):435-50. [Article]

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Drug created at October 21, 2007 12:30 / Updated at June 12, 2020 16:52