Heterocyclic steroids: Efficient routes for annulation of pentacyclic steroidal pyrimidines

Monier, M.; El‐Mekabaty, Ahmed; Abdel-Latif, D.A.; Mert, Başak Doğru; Elattar, Khaled M.

doi:10.1016/j.steroids.2019.108548

Cited by 33 publications

(19 citation statements)

References 93 publications

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“…It should be noted that some of these compounds exhibit no significant hormonal activity [28][29][30][31]. Both heterocyclic analogs I [32][33][34][35][36][37][38][39] and carbocyclic analogs II [40,41] of pentacyclic steroids have attracted considerable attention (Scheme 1). Steroids bearing an additional carbocycle annulated at the 16 and 17 positions of the ring D (III) are characterized by unique biological activity [42][43][44][45].…”

Section: Introductionmentioning

confidence: 99%

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Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Vorontsova

Yadykov

Scherbakov³

et al. 2020

Molecules

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The acid-catalyzed cyclization of benzylidenes based on 16-dehydropregnenolone acetate (16-DPA) was studied. It was found that these compounds readily undergo regioselective interrupted Nazarov cyclization with trapping chloride ion and an efficient method of the synthesis of d-annulated pentacyclic steroids based on this reaction was proposed. The structures of the synthesized pentacyclic steroids were determined by NMR and X-ray diffraction. It was found that the reaction affords a single diastereomer, but the latter can crystallize as two conformers depending on the structure. Antiproliferative activity of synthesized compounds was evaluated against two breast cancer cell lines: MCF-7 and MDA-MB-231. All tested compounds showed relatively high antiproliferative activity. The synthetic potential of the protocol developed was illustrated by the gram-scale experiment.

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Section: Introductionmentioning

confidence: 99%

“…It should be noted that some of these compounds exhibit no significant hormonal activity [ 28 , 29 , 30 , 31 ]. Both heterocyclic analogs I [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ] and carbocyclic analogs II [ 40 , 41 ] of pentacyclic steroids have attracted considerable attention ( Scheme 1 ).…”

Section: Introductionmentioning

confidence: 99%

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Vorontsova

Yadykov

Scherbakov³

et al. 2020

Molecules

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“…The anti-Alzheimer activity of some synthesized heterocyclic pyrimidine and thiopyrimidine derivatives fused with steroidal structure was reported and conveniently screened for their anti-Alzheimer activities using of Flurbiprofen as the reference drug compound (31) was demonstrated to exhibit remarkable activity and amyloid (A) lowering results [ 73 , 74 ] (Fig. 12 for compound 18-31 ).…”

Section: Introductionmentioning

confidence: 99%

Naturally Inspired Pyrimidines Analogues for Alzheimer’s Disease

Singh

Dhanawat²,

Gupta

et al. 2020

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: Alzheimer’s disease (AD) is a multifarious and developing neurodegenerative disorder. The treatment of AD is still a challenge and availability of drug therapy on the basis of symptoms is not up to the mark. In the context of the existence, which is getting worse for the human brain, is necessary to taken care of the all critical measures. The disease causes due to multidirectional pathology of the body, which demands the multi-target-directed ligand (MTDL) approach and provides a hope for the new drugs for AD, which is summarized herein with the pyrimidine based natural product inspired molecule as a lead. The review is sufficient to provide a list of chemical ingredients of the plant to cure the AD and screened them against the various potential targets of the AD. The synthesis of a highly functionalized scaffold in one step in one pot without isolating the intermediate is a challenging task, but in a few examples, we have highlighted the importance of this kind of reaction, generally known as multi-component reaction. The multi-component is widely accepted technique by the drug discovery people due to its high atom economy and it reduces multi-step process to a one-step process, so, the compounds library can be made in minimum time and cost. This review has highlighted the importance of multicomponent reactions by giving the example of active scaffolds of pyrimidine/fused pyrimidines. This would bring to the importance of the fast as well as a smart synthesis of the bio-relevant molecules.

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“…Previous modifications of steroids have mainly focused on the functionalization of the C-3/6/20 position of the steroid nucleus for screening anticancer molecules (Figure 1). More than 124 compounds have significant cytotoxic effects, with IC 50 /GI 50 values below 1 µM [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Among them, more than 52 compounds even have values below 50 nM [5,8,[12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…More than 124 compounds have significant cytotoxic effects, with IC 50 /GI 50 values below 1 µM [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Among them, more than 52 compounds even have values below 50 nM [5,8,[12][13][14][15][16][17][18]. In particular, the introduction of different heterocyclic systems into ring D, including pyri(mi)dine [15,16], thiophene, thiazole [12,13], In addition, the pyrazines and their derivatives are known to be very important structural motifs in various natural products, such as cephalostatins and ritterazines ( Figure 2) [20][21][22], and possess extremely potent anticancer activity (sub-nanomolar levels) [23,24].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Two Series of Novel A-Ring Fused Steroidal Pyrazines as Potential Anticancer Agents

Wang

Yuan

Qian

et al. 2020

IJMS

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Background: Increasingly, different heterocyclic systems have been introduced into the steroid nucleus to significantly enhance the antitumor activities of steroid molecules. However, in this study, few literature precedents describing the pyrazine heterocyclic-condensed modification to an A-ring of steroid monomers were found, although the pyrazine group is thought to be essential for the potent anticancer activity of clinically relevant drugs and natural steroid dimers. Methods and Results: Two series of novel A-ring fused steroidal pyrazines were designed and efficiently synthesized from commercially available progesterone via key α-ketoenol intermediates. Through a cell counting kit-8 cytotoxic assay of 36 derivatives for three tumor cells, 14 compounds displayed significant antiproliferative activity compared to 5-fluorouracil, especially for human prostatic tumor cells (PC-3) in vitro. Further mechanistic studies indicated that the most active compound, 12n (IC 50 , 0.93 µM; SI, 28.71), could induce the cell apoptosis of PC-3 cells in a dose-dependent manner and cause cell cycle arrest in the G2/M phase. The molecular docking study suggested that compound 12n fitted the active sites of cytochrome P450 17A1 (6CIZ) well. Conclusions: 12n might serve as a promising lead compound for the development of novel anticancer drugs. This facile ring-closing strategy may provide a novel and promising avenue for the cycloaddition reaction of the steroidal skeleton through α-ketoenol intermediates.

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Heterocyclic steroids: Efficient routes for annulation of pentacyclic steroidal pyrimidines

Cited by 33 publications

References 93 publications

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Naturally Inspired Pyrimidines Analogues for Alzheimer’s Disease

Design, Synthesis, and Biological Evaluation of Two Series of Novel A-Ring Fused Steroidal Pyrazines as Potential Anticancer Agents

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