ChemInform Abstract: Synthesis and Pharmacology of Antiinflammatory Steroidal Antedrugs

Khan, Madeeha; Lee, Henry J.

doi:10.1002/chin.200919235

Cited by 4 publications

(4 citation statements)

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“…182 But the major side effects such as osteoporosis, growth retardation, and suppression of hypothalamic−pituitary−adrenal function along with immune system effects limit their long-term use in the treatment regimen. 183 Continuous efforts aimed toward the development of safer and potent anti-inflammatory agents produced some novel steroidal "antedrugs" for topical use 184,185 such as loteprednol etabonate. 186 The antedrugs, upon entering into systemic circulation, get converted into inactive metabolites and are excreted from the body.…”

Section: Steroidal Bioconjugates As Anti-inflammatory Agentsmentioning

confidence: 99%

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

Bansal

Suryan

2022

ACS Bio Med Chem Au

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Ever increasing unmet medical requirements of the human race and the continuous fight for survival against variety of diseases give birth to novel molecules through research. As diseases evolve, different strategies are employed to counter the new challenges and to discover safer, more effective, and target-specific therapeutic agents. Among several novel approaches, bioconjugation, in which two chemical moieties are joined together to achieve noticeable results, has emerged as a simple and convenient technique for a medicinal chemist to obtain potent molecules. The steroid system has been extensively used as a privileged scaffold gifted with significantly diversified medicinal properties in the drug discovery and development process. Steroidal molecules are preferred for their rigidness and good ability to penetrate biological membranes. Slight alteration in the basic ring structure results in the formation of steroidal derivatives with a wide range of therapeutic activities. Steroids are not only active as such, conjugating them with various biologically active moieties results in increased lipophilicity, stability, and target specificity with decreased adverse effects. Thus, the steroid nucleus prominently behaves as a biological carrier for small molecules. The steroid bioconjugates offer several advantages such as synergistic activity with fewer side effects due to reduced dose and selective therapy. The steroidal bioconjugates have been widely explored for their usefulness against various disorders and have shown significant utility as anticancer, anti-inflammatory, anticoagulant, antimicrobial, insecticidal/pesticidal, antioxidant, and antiviral agents along with several other miscellaneous activities. This work provides a comprehensive review on the therapeutic progression of steroidal bioconjugates as medicinally active molecules. The review covers potential biological applications of steroidal bioconjugates and would benefit the wider scientific community in their drug discovery endeavors.

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Section: Steroidal Bioconjugates As Anti-inflammatory Agentsmentioning

confidence: 99%

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

Bansal

Suryan

2022

ACS Bio Med Chem Au

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“…3 Most steroidal drugs used clinically as topical preparations are antesteroids, which are rapidly inactivated by enzymes in plasma and liver. 4,5 There are fewer commercially available ester-type prodrugs for topical application, due primarily to the lack of information on dermal metabolism and difficulties in controlling both the permeation rate and the rate of conversion of the prodrug.…”

Section: Introductionmentioning

confidence: 99%

Expression of Carboxylesterase Isozymes and Their Role in the Behavior of a Fexofenadine Prodrug in Rat Skin

Imai

Ariyoshi

Ohura

et al. 2016

Journal of Pharmaceutical Sciences

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The expression of carboxylesterase (CES) and the transdermal movement of an ester prodrug were studied in rat skin. Ethyl-fexofenadine (ethyl-FXD) was used as a model lipophilic prodrug that is slowly hydrolyzed to its parent drug, FXD (MW 502). Among the CES1 and CES2 isozymes, Hydrolase A is predominant in rat skin and this enzyme was involved in 65% of the cutaneous hydrolysis of ethyl-FXD. The similarity of the permeation behavior of ethyl-FXD in full thickness and stripped skin indicated that the stratum corneum was not a barrier to penetration. However, only FXD was observed in receptor fluid, not ethyl-FXD, presumably because of the high degree of binding of ethyl-FXD in viable skin. The rate of hydrolysis of ethyl-FXD was much faster than steady-state flux, such that the influx rate was the rate-limiting process for transdermal permeation. Although Hydrolase A levels gradually increased in skin taken from rats aged from 8 to 90 weeks, variations in the expression levels of the esterase hardly affected the conversion of prodrug. The present data suggest that the slow hydrolysis of the prodrug of an active ingredient in viable skin followed by slow diffusion of active drug may provide a useful approach to topical application.

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“…O ver the last three decades, steroids have become a prime focus of research in the field of medicinal chemistry due to their remarkable and diverse pharmacological properties, such as anticancer, 1,2 anti-inflammatory, 3,4 antiparasitic, 5 and antiviral activities. 6,7 In particular, the two steroid hormones estrone (1) and 17β-estradiol (2) ( Figure 1) attracted a lot of attention, as these two estrogens are known to be involved in the development of various cancer types such as breast, colorectal, prostate, and ovarian cancer.…”

mentioning

confidence: 99%

“…8 This led to the discovery of many different estradiol derivatives, which revealed to possess promising anticancer activity. In 2003, fulvestrant (3), an estrogen receptor antagonist, was approved in the USA for the treatment of hormone-related breast cancer, and since then it has been used in clinics. 9 2-Methoxyestradiol (4), an endogenous metabolite of 17β-estradiol (2), turned out to effectively inhibit cancer cell proliferation both in vitro and in vivo and is currently investigated in advanced phases of clinical trials.…”

mentioning

confidence: 99%

Synthesis of Artemisinin–Estrogen Hybrids Highly Active against HCMV, P. falciparum, and Cervical and Breast Cancer

Fröhlich

Kiss

Wölfling

et al. 2018

ACS Med. Chem. Lett.

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Artemisinin−estrogen hybrids were for the first time both synthesized and investigated for their in vitro biological activity against malaria parasites (Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a panel of human malignant cells of gynecological origin containing breast (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A). In terms of antimalarial efficacy, hybrid 8 (EC 50 = 3.8 nM) was about two times more active than its parent compound artesunic acid (7) (EC 50 = 8.9 nM) as well as the standard drug chloroquine (EC 50 = 9.8 nM) and was, therefore, comparable to the clinically used dihydroartemisinin (6) (EC 50 = 2.4 nM). Furthermore, hybrids 9−12 showed a strong antiviral effect with EC 50 values in the submicromolar range (0.22− 0.38 μM) and thus possess profoundly stronger anti-HCMV activity (approximately factor 25) than the parent compound artesunic acid (7) (EC 50 = 5.41 μM). These compounds also exerted a higher in vitro anti-HCMV efficacy than ganciclovir used as the standard of current antiviral treatment. In addition, hybrids 8−12 elicited substantially more pronounced growth inhibiting action on all cancer cell lines than their parent compounds and the reference drug cisplatin. The most potent agent, hybrid 12, exhibited submicromolar EC 50 values (0.15−0.93 μM) against breast cancer and C33A cell lines.

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ChemInform Abstract: Synthesis and Pharmacology of Antiinflammatory Steroidal Antedrugs

Cited by 4 publications

References 1 publication

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

Expression of Carboxylesterase Isozymes and Their Role in the Behavior of a Fexofenadine Prodrug in Rat Skin

Synthesis of Artemisinin–Estrogen Hybrids Highly Active against HCMV, P. falciparum, and Cervical and Breast Cancer

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