Biotin-functionalized hypoxia-responsive flavonol prodrugs as complementary imaging and antitumor leads for colon cancer.

Abstract

Tumor hypoxia provides an endogenous trigger for selective prodrug activation, but many small-molecule systems still show inadequate tumor accumulation and insufficient separation between imaging and therapeutic performance. Here, we designed and synthesized twelve biotin-functionalized, azobenzene-linked flavonol prodrugs (QC-1-QC-12) and evaluated their photophysical properties, azoreductase responsiveness, antiproliferative activity, cellular effects, tumor-associated fluorescence, and antitumor efficacy. QC-7 exhibited a concentration-dependent optical response to azoreductase, and HPLC and HRMS analyses supported the release of the fluorogenic flavonol fragment 8g. In HCT116 cells under hypoxia, QC-7 produced time-dependent fluorescence that exceeded that of 8g, and tumor-associated fluorescence remained detectable at 24 h after intravenous administration. QC-8 was the most active therapeutic candidate, with IC50 values of 16.1 ± 1.1 μM under normoxia and 6.7 ± 0.3 μM under hypoxia. Preliminary structure-activity analysis indicated that flavonol B-ring substitution influenced antiproliferative activity and contributed to the functional differentiation of the imaging and therapeutic leads. QC-8 increased G2/M-phase accumulation, promoted apoptosis-associated changes, reduced cell migration and invasion, and suppressed tumor growth in an exploratory HCT116 xenograft study. Body weight, serum biochemical parameters, and major-organ histology indicated favorable short-term tolerability at the tested doses.

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