Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway

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Abstract

Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or non-existent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, which activates the transcription of many genes that cause cell proliferation, metastasis, increased glycolysis and angiogenesis. Increased HIF expression has been linked with poor patient prognosis, increased malignancy, and therapeutic resistance. Previous work in our lab has identified 1 and 2 as inhibitors of the HIF pathway, specifically as disrupters of the p300-HIF-1α complex formation. A library of sulfonamide analogs has been designed and synthesized with the intent of examining the SAR of this series of compounds and improving potency and physicochemical properties as compared with lead compounds 1 and 2. At the end, we have achieved a thorough understanding of the structural features critical for future optimization work.

Section snippets

Class 1A

Class 1A analogs were designed to probe the importance of the features of the phenyl A ring to the activity of 1 (Table 2). The first part of the A ring examined was the double bond in the pyran ring. In many cases, double bonds are not preferred in therapeutics because of the possibility of activation and/or metabolism by cytochrome P450 (CYP) monooxygenases in the liver, which can lead to hepatotoxicity in vivo.11 For 3a (IC50 = 0.98 μM), the hydrogenated analog of 1, removal of the double bond

Class 1B

Class 1B analogs were designed to probe the activity of the moieties on the C ring (Table 3). In our previous work, it was determined that removing the 3′-methoxy group from the C ring resulted in little to no loss of activity (4e, IC50 = 0.6 μM).10 We further probed the activity of this site by removing the 4′-methoxy, 4a (IC50 = 1 μM), which resulted in a small 1.7-fold decrease in activity. Next the 4′-monomethoxy was substituted for a 4′-trifluoromethoxy moiety, 4b (IC50 = >5 μM), which resulted in

Class 1C

Class 1C analogs were designed to further probe the activity of the B and C rings and to try to introduce more polar groups in order to lower the clog P (Table 4). Although 5k (IC50 = 4 μM) had a clog P of 3.7, it demonstrated a significant loss of activity. These results support our previous computational model, that suggests that the B ring points into a hydrophobic pocket.12 Some of these analogues are hybrid 1/2 compounds, with the A ring from 1 and the B ring from 2 (5af). In this combination,

Class 2A

Class 2A analogs were designed to probe the importance of the features of the A ring to the activity of 2 (Table 5). The first strategy was to remove the fused ring feature altogether and determine whether a simple phenyl ring with various substituents would have activity. Unfortunately, only one such compound, 6b (IC50 = 3.9 μM), with a 4-methoxyphenyl A ring had any activity, and this activity was diminished by almost 14-fold from 2. 6a, cf (IC50 = >5 μM) were considered inactive, which

Class 2B

Class 2B analogs (Table 6) were designed to further probe the importance of the B and C rings to the activity of 2. None of the compounds with the conserved reduced A ring of 2 (7ac) showed improved activity over 2; the best compound 7a (IC50 = 1.8 μM), with the 3′-methoxy removed, still lost potency by 6.4-fold, whereas a similar analog to 1 (4e) did not lose activity. It is interesting that 7d (IC50 = 0.25 μM), the hydrogenated form of 2, demonstrated slightly better activity compared to 2.

Acknowledgments

Financial support from the NIH (CA180805, CA116804) is gratefully acknowledged. We also thank the GSU MBD and CDT programs for fellowships to SKZ, and a Department of Education GAANN grant (P200A120122) with Barbara Baumstark as the Principal Investigator in support of JF.

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