With the aim of developing
new effective topoisomerase IIα-targeted
anticancer agents, we synthesized a series of hydroxy- and halogenated
2,4-diphenyl indeno[1,2-b]pyridinols using a microwave-assisted
single step synthetic method and investigated structure–activity
relationships. The majority of compounds with chlorophenyl group at
2-position and phenol group at the 4-position of indeno[1,2-b]pyridinols exhibited potent antiproliferative activity
and topoisomerase IIα-selective inhibition. Of the 172 compounds
tested, 89 showed highly potent and selective topoisomerase
IIα inhibition and antiproliferative activity in the nanomolar
range against human T47D breast (2.6 nM) cancer cell lines. In addition,
mechanistic studies revealed compound 89 is a nonintercalative
topoisomerase II poison, and in vitro studies showed it had promising
cytotoxic effects in diverse breast cancer cell lines and was particularly
effective at inducing apoptosis in T47D cells. Furthermore, in vivo
administration of compound 89 had significant antitumor
effects in orthotopic mouse model of breast cancer.
One
of the three subtypes of the peroxisome proliferator-activated
receptor (PPAR) functioning as a transcription factor is the PPARβ
or PPARδ. PPARδ is crucial to pathophysiological processes,
including metabolic disorders, liver diseases, and cardiovascular
diseases. In the past, the clinical development of PPARδ-selective
agonist drugs has been stalled due to potential safety-related issues.
Despite the elusiveness of such a drug, efforts continue in developing
drugs that target PPARδ due to advances in the knowledge of
the PPARδ receptor’s structure and functions. While several
preclinical and clinical studies are reported on PPARδ agonists,
there is limited data with no clinical evidence available for PPARδ-selective
antagonists. In this review, we mainly focus on the challenges of
PPARδ selectivity and the medicinal chemistry of most active
agonists discovered by different pharmaceutical companies and institutes.
With this in mind, we also provide an update on the development status
of PPARδ agonists that are undergoing clinical trials and their
therapeutic promise for the treatment of various diseases.
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