Title:Performance of Green Desymmetrization Methods toward Bioactive
Cephalostatin Analogues
Volume: 31
Issue: 22
Author(s): Mansour Nawasreh*Lubna Tahtamouni
Affiliation:
- Scientific Basic Sciences Department, Faculty of Engineering Technology, Al-Balqa Applied University, Marka 11134, Amman, Jordan
Keywords:
Cephalostatin, desymmetrization, bis-steroidal pyrazine, symmetrical coupling, chemoselectivity, ERmediated apoptosis, chemoresistance.
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 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.
