Biotransformation of dehydroepiandrosterone with <i>Macrophomina phaseolina</i> and β-glucuronidase inhibitory activity of transformed products

Choudhary, M. Iqbal; Zafar, Saima; Khan, Niaz Ali; Ahmad, Saeed; Noreen, Shagufta; Marasini, Bishnu P.; Al-Khedhairy, Abdulaziz A.; Atta-ur-Rahman, _

doi:10.3109/14756366.2011.590804

Cited by 29 publications

(6 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, naturally occurring androstane steroid hormone, 5-dehydroepiandrosterone (47, Fig. 8) and its Macrophomina phaseolina metabolites were examined for their bGLU inhibitory potentials [155]. The inferior potency/inactivity of metabolites compared to parent 5-dehydroepiandrosterone (IC 50 ¼ 77.9 mM) suggests that having an alkene unit at position-5 and cyclopentanone unit in the molecular architecture is crucial to inhibitory potency.…”

Section: Terpenoids and Steroidsmentioning

confidence: 99%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

107

View full text Add to dashboard Cite

BiomarkerEnzyme inhibition Molecular target Structure activity relationship a b s t r a c tThe emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, b-glucuronidase (bGLU) e a lysosomal acid hydrolase responsible for the catalytic deconjugation of b-D-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of bGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of bGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved bGLU inhibitory potency and the development of new therapeutic agents in consequential.

show abstract

Section: Terpenoids and Steroidsmentioning

confidence: 99%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

107

View full text Add to dashboard Cite

show abstract

“…In continuation of our recent work on the microbial transformation of important steroids [2], we investigated the microbial biotransformation of DHT. The rationale was to produce the DHT analogues for studying the structure-activity-relationship (SAR) and to synthesize medicinally important compounds with novel activities.…”

Section: Introductionmentioning

confidence: 99%

Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone

Zafar

Choudhary

Dalvandi

et al. 2013

Chemistry Central Journal

Self Cite

View full text Add to dashboard Cite

BackgroundBiotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites.ResultsMicrobial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5α-androstan-3β,17β-diol (2), and 5β-androstan-3α,17β-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11α,17β-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11α-hydroxyandrost-4-en-3,17-dione (6), 11α-hydroxyandrost-1,4-dien-3,17-dione (7), 12β-hydroxyandrost-1,4-dien-3,17-dione (8), and 16α-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5–7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities.ConclusionBiotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5–7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer’s disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced.

show abstract

“…Macrophomina phaseolina and Fusarium lini (Figures 1 and 2). M. phaseolina is previously reported to catalyze the introduction of double bond between C-1 and C-2, hydroxyl groups at C-6, C-15, C-16 and C-17, and carbonyl group at C-17 of the steroidal skeleton [1,20]. F. lini is also reported to catalyze the oxidation at C-1, C-2, C-6, and C-11 of steroidal skeleton [21].…”

Section: Resultsmentioning

confidence: 99%

“…Microbial transformation of steroids has been extensively employed for the synthesis of steroidal drugs, both at laboratory and industrial levels [1-7]. In modern drug discovery process, generation of libraries of bioactive compounds with diverse structures plays an important role [8].…”

Section: Introductionmentioning

confidence: 99%

Microbial transformation of anti-cancer steroid exemestane and cytotoxicity of its metabolites against cancer cell lines

Baydoun

Bibi

Iqbal

et al. 2013

Chemistry Central Journal

View full text Add to dashboard Cite

BackgroundMicrobial transformation of steroids has been extensively used for the synthesis of steroidal drugs, that often yield novel analogues, not easy to obtain by chemical synthesis. We report here fungal transformation of a synthetic steroidal drug, exemestane, used for the treatment of breast cancer and function through inhibition of aromatase enzyme.ResultsMicrobial transformation of anti-cancer steroid, exemestane (1), was investigated by using two filamentous fungi. Incubation of 1 with fungi Macrophomina phaseolina, and Fusarium lini afforded three new, 11α-hydroxy-6-methylene-androsta-1, 4-diene-3,17-dione (2), 16β, 17β-dihydroxy-6-methylene-androsta-1, 4-diene-3-one (3), and 17β-hydroxy-6-methylene-androsta-1, 4-diene-3, 16-dione (4), and one known metabolites, 17β-hydroxy-6-methylene-androsta-1, 4-diene-3-one (5). Their structures were deduced spectroscopically. Compared to 1 (steroidal aromatase inactivator), the transformed metabolites were also evaluated for cytotoxic activity by using a cell viability assay against cancer cell lines (HeLa and PC3). Metabolite 2 was found to be moderately active against both the cell lines.ConclusionsBiotransformation of exemestane (1) provides an efficient method for the synthesis of new analogues of 1. The metabolites were obtained as a result of reduction of double bond and hydroxylation. The transformed product 2 exhibited a moderate activity against cancer cell lines (HeLa and PC3). These transformed products can be studied for their potential as drug candidates.

show abstract

Biotransformation of dehydroepiandrosterone with Macrophomina phaseolina and β-glucuronidase inhibitory activity of transformed products

Cited by 29 publications

References 51 publications

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone

Microbial transformation of anti-cancer steroid exemestane and cytotoxicity of its metabolites against cancer cell lines

Contact Info

Product

Resources

About