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1.
Curr Med Chem ; 2023 May 08.
Article in English | MEDLINE | ID: mdl-37157200

ABSTRACT

Since the discovery of cephalostatins, which have shown remarkable activity against human cancer cells, they have attracted the attention of researchers to target the synthesis of such impressive, complicated molecules using the green desymmetrization approach. In the current review, we report the progress in the desymmetrization of symmetrical bis-steroidal pyrazines (BSPs) as an approach toward potentially active anti-cancer agents, namely cephalostatins/ ritterazines. The achievement of synthesizing a gram-scaled prodrug with comparable activity to the potent natural cephalostatins using green methods is our primary target. These synthetic methods can be scaled up based on the symmetrical coupling (SC) of two steroidal units of the same type. Our secondary target is the discovery of new green pathways that help in structural reconstruction programming toward the total synthesis of at least one potentially active family member. The strategy is based on functional group interconversions with high flexibility and brevity using green selective methods. The introduction of controlling groups using nontrivial reconstruction methodologies forms the backbone of our work. After certain modifications to the symmetrical BSP starting material, the resulting analogs underwent several chemoselective transformations through three main routes in rings F, D, and C. One of these routes is the chemoselective spiroketal opening (ring-F). The second route was the functionalization of the ∆14,15 bond (ring-D), including chlorination/dechlorination, in addition to epoxidation/ oxygenation processes. Finally, the introduction of the C-11 methoxy group as a directing group on ring-C led to several chemoselective transformations. Moreover, certain transformations on C-12 (ring-C), such as methylenation, followed by hydroboration-oxidation, led to a potentially active analog. The alignment of these results directs us toward the targets. Our efforts culminated in preparing effective anti-cancer prodrugs (8, 24, 30, and 31), which are able to overcome cancer drug resistance (chemoresistance) by inducing the atypical endoplasmic reticulum-mediated apoptosis pathway, which works through the release of Smac/Diablo and the activation of caspase-4.

2.
Steroids ; 158: 108602, 2020 06.
Article in English | MEDLINE | ID: mdl-32092307

ABSTRACT

Cephalostatin 1, a potent anti-cancer agent, is a natural bis-steroidal alkaloid that causes cell death in the subnanomolar to picomolar ranges via an atypical apoptosis pathway. Although cephalostatin 1 is a highly effective anticancer drug, its availability limits its utilization. We previously reported the synthesis of two 12'α-hydroxy derivatives of cephalostatin 1 that induce cell death by activating the ER stress apoptosis signaling pathway. For the current work, we synthesized six C11-functionalized cephalostatin 1 analogues (CAs) to evaluate their biological activity. For the cytotoxic compounds, the induced apoptotic pathway was investigated. The C11-functionalized cephalostatin 1 analogues 5 and 6 (CA5 and CA6) were found to exhibit cytotoxic activity against K-562 leukemia cells, MCF-7 breast cancer cells and DU-145 prostate cancer cells, while the remaining four analogues did not show anti-tumor activities against any of the cell lines. Our results indicated that CA5 and CA6 induced cell death via the atypical ER-dependent apoptosis pathway; they increased the expression of Smac/DIABLO, an inhibitor of inhibitors of apoptosis (IAPs), which in turn facilitated the activation of different caspases including the ER-caspase 4 without cytochrome c release from mitochondria. CA5 and CA6 are promising anticancer agents due to their low GI50, the remarkable apoptosis pathway they induce which can overcome chemoresistance, and their very low toxicity to normal cells making them cephalostatin 1 utilizable alternatives.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Phenazines/chemistry , Phenazines/pharmacology , Signal Transduction/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Steroids/chemistry , Steroids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , K562 Cells , MCF-7 Cells , Molecular Conformation , Phenazines/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids/chemical synthesis , Tumor Cells, Cultured
3.
Heliyon ; 6(1): e03025, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31909240

ABSTRACT

Herewith, we report on a method that allows to simultaneously protect both the ∆14,15 bond and the carbonyl group of the symmetrical bis-steroidal diketone 2. We found that environmentally friendly and gas-free chlorination is ideally suited to achieve this goal. This method was discovered during our efforts to methoxylate 2 in a solution of dichloromethane and basic methanol in the presence of diacetoxy iodobenzene. Unexpectedly, the ∆14,15 bonds were chlorinated once as well as twice in a statistical manner. Interestingly, the singly dichlorinated desymmetrized product is an ideal precursor for conduction a series of position selective transformations. Importantly, the carbonyl group present in the nonchlorinated hemisphere can be selectively reduced, olefinated or oximated, while the other carbonyl group stays unaltered. A structurally related "monomeric" steroid derivative undergoes ∆14,15 chlorination and 11-position methoxylation under same conditions. These findings represent a powerful entry for preparing new nonsymmetrical cephalostatin derivatives.

4.
Eur J Pharmacol ; 818: 400-409, 2018 Jan 05.
Article in English | MEDLINE | ID: mdl-29154934

ABSTRACT

The current study was conducted to compare the cytotoxicity of two stereospecific cephalostatin 1 analogues (CAs) against several human normal cell types and cancer cell lines and to determine their cytotoxic mechanism. Both CA analogues induced apoptosis and were cytotoxic with 50% growth inhibition (GI50) at ~1µM or less in six human cancer cell lines but neither analogue at 10µM killed more than 14% of any of three types of normal human cells suggesting their cytotoxicity is cancer-specific. CA treatment inhibited clonogenic tumor growth and activated caspase 3 and 9 but not caspase 8. CA-induced apoptosis was inhibited by the pan caspase inhibitor indicating the importance of caspase activation. CA treatment released smac/DIABLO but not cytochrome c from mitochondria and induced phosphorylation of eIF-2 and the activation of procaspase 4 in cancer cells, similar to cell treatment with thapsigargin, a known endoplasmic reticulum (ER) stress inducer. Finally, cells pretreated with a caspase 4 inhibitor were resistant to CA-induced apoptosis. In conclusion, both CAs induced apoptosis by triggering ER stress. Because of their ease of synthesis and low GI50, these cephalostatin analogues represent promising anticancer drugs.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Phenazines/chemistry , Phenazines/pharmacology , Signal Transduction/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Steroids/chemistry , Steroids/pharmacology , Apoptosis Regulatory Proteins , Caspases, Initiator/metabolism , Cell Proliferation/drug effects , Enzyme Activation/drug effects , Humans , Intracellular Signaling Peptides and Proteins/metabolism , K562 Cells , MCF-7 Cells , Mitochondrial Proteins/metabolism
5.
Reprod Med Biol ; 5(4): 269-276, 2006 Dec.
Article in English | MEDLINE | ID: mdl-29699256

ABSTRACT

Aims: The aim of the present study was to determine the effect of orchid bulbs on the reproductive system of male albino mice. Methods: Orchid bulb extract was fed to 20 male albino mice (5 g/mouse/day) for 35 days and compared with a similar number of mice as controls. Total testicular germ cell population, histometrical parameters, serum blood biochemistry and hormonal assay were determined. Results: The ingestion of orchid bulb by mice induced a significant increase in the following parameters: (i) testes and seminal vesicle weights; (ii) number of different testicular germ cell population including interstitial Leydig cells and fibroblasts; and (iii) testicular cell linage dynamics obtained from testes and cauda epidydimides. An important finding was that the ingestion of the orchid diet by male mice increased their fertility. This was indicated by an elevation in the number of impregnated females when allowed to mate with treated mice, an increase in the impregnation sites, and an increase in the number of viable fetuses and the offspring's male/female ratio. A slight significant increase in the testosterone and follicular stimulating hormone titers in the treated mice were found in their blood serum. In contrast, a decrease in the number of degenerating cells was observed. Conclusions: Orchid bulb treatment might play an important role in improving male reproductive potential and fertility. (Reprod Med Biol 2006; 5: 269-276).

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