Synthesis, biosynthesis and biological activities of galbanic acid – A review

Figures & data

Figure 1. Chemical structures of galbanic acid (R = H) and methyl galbanate (R = CH₃).

Table 1. Tabulated overview of the biological activities of galbanic acid and methyl galbanate.

Biological activity	Organism/enzyme/cell line	Tested concentrations/IC50/MIC	Results	Ref.
Anticoagulant	Dog	50, 100, 200 µg/mL	GA showed platelet aggregation suppression.	(Mansurov & Martirosov, 1988, 1990)
Farnesyltransferase (Ftase) inhibitory effect	Farnesyltransferase (Ftase)	IC50 2.5 µM	Exhibited a significant inhibition in a dose dependent manner, in vitro	(Cha et al., 2011)
Acetylcholinesterase (AchE) inhibitory effect	Human erythrocyte acetycholinesterase	100 µM	GA showed 19.1 ± 6% inhibition	(Karimi et al., 2010)
Inhibition of efflux phenomenon in bacteria	Staphylococcus aureus	300 µg/mL	The rate of ethidium bromide accumulation in clinical isolates was enhanced by galbanic acid (300 μg/ml). Galbanic acid inhibited the efflux of ethidium bromide in the same manner as verapamil did.	(Fazly-Bazzaz et al., 2009)
P-glycoprotein   inhibitory effect	MCF7/Adr cell line	5, 10 and 25 μg/mL	The effect of galbanic acid was more potent than the one of the typical P-gp inhibitor, verapamil (galbanic acid IC50: 5.6 μg/mL)	(Hanafi-Bojd et al., 2011)
Cancer chemopreventive	Raji cells inoculated by Epstein-Barr Virus Early Antigen (EBV-EA)	methyl galbanate, IC50 11.7 nM galbanic acid, IC50 11.8 nM	GA and methyl galbanate showed valuable antitumor-promoting effects in prophylaxis of cancer	(Iranshahi et al., 2008)
Cytotoxic	Prostate cancer cells	20 μM	GA down-regulated androgen receptor protein abundance and signaling and showed a comparable inhibitory efficacy as androgen deprivation	(Zhang et al., 2012)
Antibacterial	Staphylococcus aureus	100 µg/mL	GA significantly improved antibiotic efficacy against S. aureus when combined with penicillin G and cephalexin	(Shahverdi et al., 2007)
Antileishmanial	Leishmania major promastigote	IC50 164.8 µM	GA showed a weak inhibitory effect against promastigotes of L. major	(Iranshahi et al., 2007)
Antiviral	Influenza A virus (H1N1)	Galbanic acid IC50 0.45 µg/mL Methyl galbanate IC50 0.26 µg/mL	GA and methyl galbanate exhibited a higher antiviral potency than amantadine as a positive control (IC50 0.92 µg/mL)	(Zhang et al., 2012)
Improved    experimental hepatitis	Rat	50 mg/kg (orally)	A more rapid restoration of intensity of bile secretion, synthesis of bile acids and bilirubin, cholesterol excretion were observed as compared with control in the animal	(Syrov et al., 1990)
Anti-inflammatory	RAW264.7 cells	GA 10 µM Methyl galbanate 10 µM	GA showed no effect on NO production; Methyl galbanate significantly inhibited NO production; Methyl galbanate exerts its anti-inflammatory effect by inhibiting iNOS mRNA expression	(Kohno et al., 2011)

Figure 2. Timeline of the proposed structures of galbanic acid by date.

Figure 3. Simplified synthesis and biosynthesis of galbanic acid.

Figure 4. Marner’s and Appendino’s proposals for biosynthesis of galbanic acid.

Figure 5. Synthesis of galbanic acid from 7-hydroxycoumarin (umbelliferone) and R-pulegone. Lithium diisopropyl amine, LDA; Tertiary butyldimethylsilyl chloride, TBSCl; Pyridium chlorochromate, PCC; p-Toluenesulfonyl chloride, p-TSCL; Microwave-assisted, MW.

Figure 6. Improved synthesis of galbanic acid. Diisopropyl azidocarboxylate, DIAD.

Table 2. In silico physico-chemical properties of galbanic acid, galbanic acid sodium salt and methyl galbanate.

	MW	NROT	HBA	HBD	PSA	cLog P	Log D5.5	Bioavailability prediction
GA	398	6	4	1	72.83	4.83	3.78	√
GA methyl ester	412	7	3	0	61.83	4.98	4.98	√
GA sodium salt	420	6	4	0	75.66	1.59	3.01	√

For oral bioavailability, NROT, HBA, HBD, cLogP, PSA and MW should be less than 10, 10, 5, 5, 140 and 500, respectively. Log D_5.5 is defined as Log P at pH 5.5 (pH of the small intestine) and is a more appropriate measure than Log P where oral drug absorption occurs. All physicochemical parameters used for the prediction of drug-likeness were calculated using MarvinSketch (version 5.11, academic package, ChemAxon).

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