Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition

To cope with hypoxia, tumor cells
have developed a number of adaptive
mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote
angiogenesis and cell survival. Due to significant roles of HIF-1
in the initiation, progression, metastasis, and resistance to treatment
of most solid tumors, a considerable amount of effort has been made
to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B
(2) are potent inhibitors of HIF-1 activity. To define
the structural requirements of manassantins for HIF-1 inhibition,
we prepared and evaluated a series of manassantin analogues. Our SAR
studies examined key regions of manassantin’s structure in
order to understand the impact of these regions on biological activity
and to define modifications that can lead to improved performance
and drug-like properties. Our efforts identified several manassantin
analogues with reduced structural complexity as potential lead compounds
for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression
of the HIF-1α protein and reduced the levels of HIF-1 target
genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial
growth factor (VEGF). These findings provide an important framework
to design potent and selective HIF-1α inhibitors, which is necessary
to aid translation of manassantin-derived natural products to the
clinic as novel therapeutics for cancers.