Cancer is one of the difficult-to-treat diseases, and is characterized by abnormal/ uncontrolled growth of cells.1 Development of resistance towards chemotherapeutic agents often leads to treatment failure. One of the ways to thwart/delay resistance development is to use a multi-mechanistic approach through drug combinations or hybrid drugs.2 Among therapeutically useful scaffolds, those with vicinal diaryls form a special group with diverse biological activities such as anticancer, antiviral, antimicrobial, anti-inflammatory, analgesic, etc.3 As part of our interest in this area, we have investigated the reactions of indolizinones with dimethyl acetylenedicarboxylate, which gave direct access to 3’,8a-dihydrocyclopenta[hi]indolizin-8a-ol (1) and 1H-pyrrol-3(2H)-one (2) through [8+2] and [4+2] modes of cycloadditions.4a The former group on treatment with HBF4.Et2O led to the formation of a new class of strained cyclazine analogs (3) in which the central position is occupied by an sp3 carbon.4b This observation also motivated us to devise a synthetic route towards Discoipyrrole C and its analogs as well as their hybrids (4) with Combretastatin A-4.4c Synthesis of quinolone-pyrrolone hybrids (5) is another important achievemet.4d Synthetic details and biological activities of these compounds will be discussed during this presentation.


Figure 1. (a) Structures of novel vicinal diary heterocycles. (b) X-ray structure of 1
References:
(1) Jordan, M.A.; Wilson, L. Nat. Rev. Cancer, 2004, 4, 253–265.
(2) Szumilak, M.; Wiktorowska-Owczarek, A.; Stanczak A.; Molecules 2021, 26, 2601.
(3) Barmade, M. A.; Ghuge, R. B. Elsevier Ltd., 2018. DOI:10.1016/b978-0-08-102237-5.00001-8.
(4) (a) Kurian, J.; Muraleedharan, K, M.; Org. Biomol. Chem. 2019, 17, 8832-8848. (b) Kurian, J.; Shurooque, K. S.; Ramkumar, V.; Chakkumkumarath L.; Muraleedharan, K, M.; Kannoth, M.M. Org. Lett. 2021, 23, 3354−3358. (c) Kurian, J.; Muraleedharan, K, M (Manuscript under preparation). (d) Kurian, J.; Muraleedharan, K, M (Manuscript under preparation)