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Performance of Green Desymmetrization Methods toward Bioactive Cephalostatin Analogues#


Mansour Nawasreh* and Lubna Tahtamouni   Pages 1 - 18 ( 18 )


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 Δ14,15 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. #This work is dedicated to Professor Helmut Duddeck-Leibniz Hannover University on his 77th Birthday on 19.06.2023.


Cephalostatin, desymmetrization, bis-steroidal pyrazine, symmetrical coupling, chemoselectivity, ERmediated apoptosis, chemoresistance.


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