Novel double functional protection of cephalostatin analogues using a gas-free chlorination method

Nawasreh, Mansour; Kirschning, Andreas; Duddeck, H.; Dräger, Gerald; Fenske, Dieter

doi:10.1016/j.heliyon.2019.e03025

Cited by 2 publications

(1 citation statement)

References 20 publications

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“…This can be rationalized based on the almost 90°‐ dihedral angle between them. This is similar to a recently reported case that appeared when the double bond was chlorinated and the structure was approved by X‐ray diffraction [17] . This result helps to ensure the α‐configuration of the epoxy group.…”

Section: Resultssupporting

confidence: 89%

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

Nawasreh

2022

ChemistrySelect

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Cephalostatins (e. g. cephalostatin 1) are a class of natural products that exert extraordinary antitumor activity with the presence of a significant number of oxygen atoms either in etheric, alcoholic, or epoxydic form. Here, we describe a novel epoxidation method of ▵14,15 bond of the symmetrical bis‐steroidal pyrazine (BSP) (the diketone 2) using only grounded lithium metal in dry THF. This chemo and regioselective method which forms an environmentally begin solved one of the major challenges that overcome the N‐oxide formation in BSP's. The epoxidized products underwent a regioselective reduction with sodium borohydride NaBH4 yielding 15α‐hydroxy derivatives. Interestingly, the triol derivative 5 was found to exert a powerful activity against the three selected cancer cell lines: K562, MCF‐7, and DU‐145 using MTT assay (average GI50<0.1 μM). Noteworthy, the BSP 7 (with vicinal‐diol functionality) was obtained when the epoxidized derivatives 4 was treated with sodium metal in dry THF.

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Section: Resultssupporting

confidence: 89%

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

Nawasreh

2022

ChemistrySelect

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Performance of Green Desymmetrization Methods toward Bioactive Cephalostatin Analogues

Nawasreh

Tahtamouni

2024

CMC

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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.

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Novel double functional protection of cephalostatin analogues using a gas-free chlorination method

Cited by 2 publications

References 20 publications

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

Performance of Green Desymmetrization Methods toward Bioactive Cephalostatin Analogues

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