Heterocyclic Steroids Research Articles

Syntheses and medicinal chemistry of spiro heterocyclic steroids.

There is compelling evidence that incorporating a heterocyclic moiety into a steroid can alter its pharmacological and pharmacokinetic properties, driving intense interest in the synthesis of such hybrids among research groups. In this review, we present an overview of recent synthetic methodologies, spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being predominant. The outlined synthetic procedures emphasize the pivotal steps for constructing the heterocycles, often accompanied by a detailed account of the overall synthesis pathway. The review encompasses innovative compounds, including bis-steroids linked by a spiro heterocycle and steroids conjugated to heterocyclic moieties containing three or more (hetero)cycles. Moreover, many compounds are accompanied by data on their biological activities, such as antiproliferative, antimalarial, antimicrobial, antifungal, steroid antagonist, and enzyme inhibition, among others, aimed at furnishing pertinent insights for the future design of more potent and selective drugs.

Anti-cancer activity, and molecular docking of novel hybrid heterocyclic steroids revealed promising anti-hepatocellular carcinoma agent: Implication of cyclin dependent kinase-2 pathway.

To identify new steroidal agents with potential biological activities, we synthesized hybrid steroids containing thiazole, pyrazole, isoxazole, thiophene or phthalazine moiety. Epi-androsterone 1 reacted with phenylthiosemicarbazide to afford the corresponding androstane-4-phenyl-3-thiosemicarbazone derivative 2. The latter product was used in the synthesis of a series of annulated steroid derivatives. Also, Epi-androsterone 1 reacted with the thienopyridazine derivative 16 to afford the thieno[3,4-d]pyridazino-N-ylidenoandrostane derivative 17. Compound 17 reacted readily with electron-poor olefins to yield the corresponding phthalazine steroid derivatives. Detailed experimental and spectroscopic evidences for the structures of the newly synthesized compounds are explained. Compounds 3, 7, 8a, 12a, 14, 17 and 21a, were investigated individually as anticancer agents on different panel of human malignant cell lines. Moreover, a computer modelling investigation was performed to speculate the macromolecular targets for the most promising candidate. The results revealed a concentration-dependent reduction in the number of viable cells in all cancer cell lines. Most notably, compound 7 was the most effective compound against all tested cancer cell lines, especially against HepG2 cell line; therefore, the mode of action of this compound against HCC was investigated. Compound 7 was able to induce cell cycle arrest, and DNA fragmentation in HepG2 cells. Moreover, compound 7 induced apoptosis via upregulating the expression of caspase-3, -8, -9, P53, Bax and inhibiting the expression of BCL2, and CDK2 genes. Our results highlighted compound 7 as a promising anti-hepatocellular carcinoma agent, with theoretical, and practical potential binding affinity with CDK2; therefore, more investigations are required to elucidate its chemotherapeutic value as anti-HCC agent.

Synthesis and biological evaluation of 17-cyanopyridine derivatives of pregnenolone as potential anti-prostate cancer agents

A series of new 17-cyanopyridine derivatives of pregnenolone have been synthesized, and their anti-proliferative activities against different human cancer cell lines were tested. The extensive structure-activity relationship (SAR) data suggested that the introduction of 2-amino-4-aryl-3-cyanopyridine to the D ring of pregnenolone may increase the anti-cancer activity. Among the products, the most potent compound 4j exhibited good growth inhibition against all the tested cells especially for PC- 3 cells with an IC50 value of 2.0 μM. Further mechanistic studies showed that 4j inhibited the formation of cell colonies and migration, increased the level of reactive oxygen species (ROS) in PC-3 cells in a concentration-dependent manner, and induced necroptosis through the phosphorylation of receptor interacting protein 1/3 (P-RIP1/3) and phosphorylation of mixed lineage kinase domain-like protein (P-MLKL) pathway. The 17-pregnenolone cyanopyridine derivatives hold promising potential as anti-proliferative agents, and the most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity.

Could miR-34a Inhibition be Used as a Tool to Overcome Drug Resistance in MCF-7 Cells Treated with Synthesized Steroidal Heterocycles?

Background:Progesterone derivatives have explored an improved effect on human cancer cells through combination of the explored heterocycles with progesterone moiety.miRNAs have an important role in moderating cancer cell survival, proliferation and drug resistance. The current study tested the hypothesis “whether miR-34a inhibitor has a negative impact on apoptosis and angiogenesis in MCF-7 cells treated with newly synthesized progesterone derivatives”. Methods:MCF-7 cells were treated with progesterone derivatives individually and in combination with miR-34a inhibitor. miR-34a expression levels were measured in MCF-7 cells treated with progesterone derivatives using QRT-PCR. MCF-7 cells treated with progesterone derivatives individually showed increased miR-34a expression levels. miR-34a deficient cells were treated with the newly synthesized progesterone derivatives, after that, apoptotic and angiogenic gene expression levels were determined using QRT-PCR. The studied genes were as follows: apoptotic (Bcl-2, survivin, CCND1, CDC2, P53 and P21) and angiogenic (VEGF, Hif-1α, MMP-2, Ang-1, Ang-2, and FGF-1). Results:The results showed that miR-34a deficient MCF-7 cells treated with the newly progesterone derivatives still have promising effects on apoptotic and angiogenic genes. Besides, results revealed that miRNA-34a deficient MCF-7 cells exhibited improved effect of tested compounds in some apoptotic and angiogenic genes such as CDC-2, MMP-2. Conclusion:These results revealed that miR-34a inhibitor did not have remarkable negative effect on apoptosis and angiogenesis. On contrary, it showed an improved effect on some genes. And consequently, miR-34a inhibitor could be used safely as a tool to tackle drug resistance in breast cancer cells.

Augmentation of steroidal β-formylenamide with pyrazolo and benzimidazo moieties: A tandem approach to highly fluorescent steroidal heterocycles

A facile synthesis of pyrazolo[1,5-a]pyrimidine and benzimidazo[1,2-a]pyrimidine annulated steroids is described from the novel reaction of β-formyl enamides with amino pyrazoles, indazoles and benzimidazoles. Several of the products exhibited fluorescence properties with high quantum yields.

Heterocyclic steroids: Synthetic routes and biological characteristics of steroidal fused bicyclic pyrimidines

AbstractNatural steroids are characterized as a vital class of compounds, a type of secondary metabolites and components of cell membranes that widely accessible in plants or animals displayed significant pharmacological and varied biological properties. The present study aims to highlight the conveyed researches of synthetic routes adopted to obtain the various structures of steroidal fused bicyclic pyrimidines with substantial biological and pharmaceutical importance. The topic was discussed in light of the synthesis of fused [6 + 5] bicyclic systems, fused [6 + 6] bicyclic systems, binary heterocycles, and biological applications. In detail, the various synthetic strategies for the construction of steroids fused to bicyclic pyrazolopyrimidines, thiazolopyrimidines, triazolopyrimidines, pyridopyrimidines, pyranopyrimidines, and binary pyrimidines were discussed. Heterocyclic steroids of this class of compounds demonstrated potent anticancer, anti‐proliferative, anti‐neuro‐inflammatory, anti‐inflammatory, and anti‐ulcer activities. It was perceived that the synthetic steroids of such bicyclic pyrimidine scaffolds are fused into the steroid basic skeleton is essential for the potent bioactivities.

Assessment of the Antitumor Potentiality of Newly Designed Steroid Derivatives: Pre-Clinical Study.

Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa –fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.

Synthesis of Thiophenyl, Thiazolyl, and Pyridinyl Androstane Derivatives: A Novel Class of Potent Anti-inflammatory and Anti-ulcerogenic Heterocyclic Steroids

Synthesis of Thiophenyl, Thiazolyl, and Pyridinyl Androstane Derivatives: A Novel Class of Potent Anti-inflammatory and Anti-ulcerogenic Heterocyclic Steroids

Screening of different drug design tools to predict the mode of action of steroidal derivatives as anti-cancer agents

There is a pressing need to discover and develop novel drugs against cancer. With the new era of bioinformatics, which integrates different aspects, drug development has been tremendously improved. Recently, extensive research was directed towards the rational modification of steroid molecules against different disease especially cancer. Moreover, heterocyclic steroid derivatives have shown a lot of different biological activities such as antimicrobial, anti-inflammatory, and anti-cancer activities. Molecular docking methods can be used to explore how the steroid derivatives conformations can adopt within the binding sites of specific macromolecular targets involved in cancer progression. We conducted this study to investigate the accuracy of different molecular docking calculations using different steroidal molecular targets, and to define the most accurate one to study the mode of action of steroid derivatives as potential anti-cancer drugs. Our results revealed that the Dock6, PLANTS, AutoDock, GLIDE (SP and XP), and GOLD (ASP, Chemscore, and PLP) software were able to maintain the binding mode of the co-crystallized ligands inside their proteins by achieving RMSD values lower than two. Moreover, molecular docking study revealed that compound 4, and 5 are promising steroidal derivatives as anti-cancer drugs. Further on, the cytotoxic activity of the selected steroidal derivatives were tested against leukemia cell line using MTT assay. The results revealed that compound 4, and 5 were potential cytotoxic agents against THP-1 cells (IC50s were 44.67 µM, and 46.77 µM, respectively), these results are in agreement with the molecular docking study.

Photochemical Rearrangement of a 6-Azasteroid Oxaziridine to a Novel 17β-Carbomethoxy-A-homo-B-seco-6-aza-3, 5-androstanedione

4- and 6-azasteroids have been shown to be potent inhibitors of human 5α-reductase and certain azasteroids have shown significant clinical benefit in the treatment of androgen-related disorders. In an effort to expand the diversity of steroidal heterocycles synthetically accessible for structure-activity relationship exploration, a novel reaction sequence was applied to the preparation of the 6-azasteroid framework. To this end, photolysis of the oxaziridine derived from 17β-carbomethoxy-3β-triisopropylsilyloxy-6-azaandrost-5-ene (1) yielded a novel 7, 5-steroidal ring system that was evaluated for inhibition of human type 1 and 2 5α-reductase.

Steroid diversification by multicomponent reactions.

Reports on structural diversification of steroids by means of multicomponent reactions (MCRs) have significantly increased over the last decade. This review covers the most relevant strategies dealing with the use of steroidal substrates in MCRs, including the synthesis of steroidal heterocycles and macrocycles as well as the conjugation of steroids to amino acids, peptides and carbohydrates. We demonstrate that steroids are available with almost all types of MCR reactive functionalities, e.g., carbonyl, carboxylic acid, alkyne, amine, isocyanide, boronic acid, etc., and that steroids are suitable starting materials for relevant MCRs such as those based on imine and isocyanide. The focus is mainly posed on proving the amenability of MCRs for the diversity-oriented derivatization of naturally occurring steroids and the construction of complex steroid-based platforms for drug discovery, chemical biology and supramolecular chemistry applications.

Facile one-pot multicomponent synthesis and molecular docking studies of steroidal oxazole/thiazole derivatives with effective antimicrobial, antibiofilm and hemolytic properties

A series of steroidal oxazole and thiazole derivatives have been synthesized employing thiosemicarbazide/semicarbazide hydrochloride and ethyl 2-chloroacetoacetate with a simple and facile one-pot multicomponent reaction pathway. The antimicrobial activity of newly synthesized compounds were evaluated against four bacterial strains namely Gram-negative (Escherichia coliand Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Listeria monocytogenes) in addition to pathogenic fungi (Candida albicans and Cryptococcus neoformans). Bioactivity assay manifested that most of the compounds exhibited good antimicrobial activity. To provide additional insight into antimicrobial activity, the compounds were also tested for their antibiofilm activity against S. aureus biofilm. Moreover, molecular docking study shows binding of compounds with amino acid residues of DNA gyrase and glucosamine-6-phosphate synthase (promising antimicrobial target) through hydrogen bonding interactions. Hemolytic activity have been also investigated to ascertain the effect of compounds over RBC lysis and results indicate good prospects for biocompatibility. The expedient synthesis of steroidal heterocycles, effective antibacterial and antifungal behavior against various clinically relevant human pathogens, promising biocompatibility offer opportunities for further modification and potential applications as therapeutic agents.

Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents

A series of new steroidal pyridines have been synthesized through the based-promoted three-component reaction and preliminarily evaluated for their antiproliferative activity against different types of cancer cell lines. SARs studies showed that the heterocyclic rings attached to the 4-position of the pyridine ring were preferred over the phenyl rings for the activity. Among these compounds, the most potent compound exhibited good growth inhibition against all the tested cancer cells, especially for PC-3 cells with an IC50 value of 1.55 μM. Further mechanistic studies revealed that the most potent compound inhibited colony formation, migration and evasion of PC-3 cells in a concentration-dependent manner as well as induced apoptosis of PC-3 cells possibly through the mitochondria-related apoptotic pathways. Caspase-3/-9 and PARP were activated, finally leading to the apoptosis of PC-3 cells. For the androgen-sensitive (AR+) prostate cancer cell line LNCaP, the most potent compound was less potent than abiraterone with the IC50 value of 8.48 and 3.29 μM, respectively. The most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity. The synthesized steroidal pyridines contain the functional -OEt and CN groups, which could be used for further modifications for the construction of the steroid library.

Microwave-assisted MgO NP catalyzed one-pot multicomponent synthesis of polysubstituted steroidal pyridines

MgO NPs were proved to be a highly efficient catalyst for mild and clean conversion of steroids to steroidal heterocycles.

DFT/B3LYP calculations, in vitro cytotoxicity and antioxidant activities of steroidal pyrimidines and their interaction with HSA using molecular docking and multispectroscopic techniques

As a part of our continuing program on the synthesis of steroidal heterocycles, it has been prepared a series of novel steroidal pyrimidine derivatives 4–6via TMSCl, steroidal ketones (1c–3c), urea and benzaldehyde. The systems presented here, are novel scaffolds and have not been described before at 6th position of steroidal-6-one (1c–3c). Structural assignment of newly synthesized compounds was performed by DFT/B3LYP calculations as well as spectral and analytical data. The interactions of compounds (4–6) with HSA were studied by fluorescence spectroscopy, DLS, CD and molecular docking, under imitated physiological conditions. The antitumor activity has been tested in vitro against three cancer cell lines MDA-MB231 (breast carcinoma), HeLa (human cervical carcinoma), HepG2 (hepatic carcinoma) and one non-cancer normal cell lines, PBMCs (peripheral blood mononuclear cell) by MTT assay. In addition, in vitro antioxidant activity and apoptosis assay of the synthesized compounds (4–6) have also been investigated.

Synthesis, Characterization, and Evaluation of Cytotoxic Effects of Novel Hybrid Steroidal Heterocycles as PEG Based Nanoparticles

Anticancer agents featuring hybrid molecules can improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized heterocyclic steroids of promising anticancer effects loaded in polyethylene glycol (PEG)•based nanoparticles form. Several heterocyclic steroids (1-9) were synthesized via multicomponent reactions (MCRs) and confirmed via the analytical and spectral data. Compounds 1, 2, 3, 4, 5, 6, 7 and 9, were investigated individually in their free and PEG based nano-size hybrid forms as anticancer agents against three human cell lines: hepatocellular carcinoma cells (HepG2); breast cancer cells (MCF-7); and colon cancer cells (HCT116). The neutral red supravital dye uptake assay was employed. Compound 6 in its PEG based nano-size form exhibited the best cytotoxic effects against HepG2 and HCT116 cell lines, with IC50 values of 2.44 µmol/l and 2.59 µmol/l, respectively. In addition, it demonstrated a low IC50 value against MCF-7 (3.46µmol/l) cells. This study introduced promising anticancer agents acting through conversion into PEG-based nanoparticles.

Detection of stanozolol in the urine of athletes at a pg level: The possibility of passive exposure.

Stanozolol is a synthetic heterocyclic steroid with anabolic and androgenic properties, which has been abused by several high-profile professional athletes. Stanozolol is also used in veterinary medicine to increase appetite, cause weight gain and treat certain types of anemia. The detection of stanozolol metabolites in human urine for doping control purposes depends on the analytical method applied. The most commonly applied methods in the World Anti-Doping Agency (WADA)-accredited doping control laboratories are gas chromatography/high-resolution mass spectrometry (GC/HRMS) or gas chromatography-mass spectrometry (GC/MS/MS). Recently, a new method has been published and validated that makes the detection of 3′-hydroxystanozolol glucuronide in urine possible in a concentration >50-fold less compared to the above-mentioned commonly used methods. It is common practice to administer breeding animals with steroid hormones in order to enhance their growth. Athletes who consume meat containing such hormone residues may be at risk of failing a sports drug test. A randomized study in the general population consuming meat should be conducted, monitoring the levels of 3′-OH-stanozolol glucoronide in human urine, in order to determine the threshold levels of passive exposure, if any, and therefore guarantee that any adverse analytical findings reported in the urine of athlete at a pg level correspond to stanozolol abuse for enhancing performance.

Evaluation of heterocyclic steroids and curcumin derivatives as anti-breast cancer agents: Studying the effect on apoptosis in MCF-7 breast cancer cells

Anticancer agents consisting of hybrid molecules are used to improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized hetero-steroids of promising anticancer effects. Besides, the pro-apoptotic effects of new compounds were investigated extensively. Several pyrimidino-, triazolopyrimidino-, pyridazino-, and curcumin-steroid derivatives were synthesized, elucidated and confirmed using the spectral and analytical data. The synthesized hetero-steroids, compounds 9, 10, 11, 12, 13, 14, 15, 18, 20, 21, 22 and 24, were tested for their cytotoxic effects versus human breast cancer cells (MCF-7) using neutral red supravital dye uptake assay. Compound 24 (IC50=18μM) showed more inhibitory influence on MCF-7 growth. Using QRT-PCR (Quantitative real time-polymerase chain reaction), CCND1, Survivin, BCL-2, CDC2, P21 and P53, genes expression levels were investigated. The study results disclose that compounds 4, 7, 18, 24 knocked down the expression levels of CCND1, Survivin, BCL-2 and CDC2. However, P21 and P53 were up-regulated by compounds 21, 22. This study introduced promising pro-apoptotic anticancer agents acting through the modulation of key regulators of apoptosis and cell cycle genes.

Estrogen like agents as anticancer drugs : Theory , synthesis and analysis

A simple and suitable synthetic route is reported for the formation of new 2a-triazolylcholestane derivatives. The scheme involves transformation of the starting cholestanone to the corresponding azido compound and efficient conversions of 2a-azido-5a-cholestan-3-one (3).The antiproliferative activities of the synthesized 2-triazolyl-3-ketones against three human cancer cell lines were screened. but, the result was not so acceptable in cell-growth inhibition. Introduction there are a number of reactions that fulfill the Sharpless criteria, the Cu-catalysed azide-alkyne 1,3dipolar cycloaddition (CuAAC) is perhaps the best-known example of this group. The 1,2,3-triazole unit has a several advantageous properties, like high chemical stability, good hydrogen-bond-accepting ability, a strong dipole moment and an aromatic character.Therefore a number of compounds containing 1,2,3-triazoles have been reported to exert biological activity, including antibacterial, antiallergic and anti-HIV effects. We tried to synthesis of steroidal heterocycles, and we have tried to develop an effective route for the production of various 2-triazolyl derivatives of cholestanone, 4c,4g, it was decided to screen these compounds in vitro for their activities against a panel of three human cancer cell lines (HeLa, MCF7 and A431). Herein, we hope we can describe the details of the synthesis of 2a-azido-5a-cholestan-3-one (3), followed by Huisgen 1,3-dipolar cycloaddition with different terminal alkynes and subsequent reduction of the resultant triazolyl ketones. International Journal of Scientific & Engineering Research (IJSER) ISSN 2229-5518 DOI : 10.14299/ijser.thesis.2013.12

Design and synthesis of novel D-ring fused steroidal heterocycles

Using dehydroepiandrosterone as the starting material, we have synthesized a series of steroid analogs possessing a D-ring fused with heterocycles which are pyridine, imidazo [2,1-b]thiazoles or substituted thiazole imines. All the final structures are first reported and identified by NMR and MS spectroscopys, the yields of these products are moderate to good and the reaction conditions are mild. The cytotoxicity of the synthesized compounds against EC-109(human esophageal carcinoma), EC-9706(human esophageal carcinoma), MGC-803(human gastric carcinoma) were investigated.