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Abstract
Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure–activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.
Highlights
Marine natural products have attracted attention in recent years as a rich and promising source of drug candidates, especially in the field of anticancer drug discovery [1]
Structure-activity relationship studies and syntheses of the truncated natural products give us further opportunities to generate more promising drug leads with optimized activity, chemical stability, and accessibility [2,3]
Compounds exhibiting hypoxia-selective growth inhibitory activity could be novel and promising drug leads for anticancer drug development [5], and the adaptation factors of tumor cells to hypoxia environment, with particular regard to hypoxia inducible factor-1 (HIF-1), have been extensively investigated as drug targets for cancer chemotherapy
Summary
Marine natural products have attracted attention in recent years as a rich and promising source of drug candidates, especially in the field of anticancer drug discovery [1]. In our continuing search for bioactive compounds from marine organisms, we isolated dictyoceratin-C (1) [6] from the Indonesian marine sponge Dactylospongia elegans as a hypoxia-selective growth inhibitor, and found that dictyoceratin-A (2) [7] exhibited a similar biological activity (Figure 1). These two sesquiterpene phenols inhibited the proliferation of human prostate cancer DU145 cells selectively under hypoxic condition in a dose-dependent manner at concentrations ranging from 1.0 to 10 μM, by inhibiting the accumulation of HIF-1α under hypoxic condition [8]
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