Antitumor Agents. 289. Design, Synthesis, and Anti-Breast Cancer Activity in Vivo of 4-Amino-2H-benzo[h]chromen-2-one and 4-Amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one Analogues with Improved Water Solubility

Abstract

Previously, we reported that 4-amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogues, which were developed from the lead natural produce neo-tanshinlactone, are potent cytotoxic agents. In order to improve on their water solubility, the diamino analogues and related salts were designed. All synthesized compounds were assayed for cytotoxicity, and selected compounds were evaluated for in vivo anti-mammary epithelial proliferation activity in wild-type mice and mice predisposed for mammary tumors due to Brca1/p53 mutations. The new derivatives 10, 16 (ABO), 22, and 27 (ATBO) were the most active analogues with IC50 values of 0.038–0.085 μM in the cytotoxicity assay. Analogue 10 showed around 50-fold improved water solubility compared with the prior lead ABO compound 4-[(4'-methoxyphenyl)amino]-2H-benzo[h]chromen-2-one (3). Compounds 3, 4, 10, and 22 significantly reduced overall numbers of mammary cells as indicated by the reduction of mammary gland branching in mutant mice. A one-week treatment with 10 resulted in 80% reduction in BrdU-positive cells in the cancer prone mammary gland. These four compounds had differential effects on cellular proliferation and apoptosis in wild-type mouse and mouse model of human breast cancers. Compound 10 merits further development as a promising anticancer clinical trial candidate.

An improved water-soluble/stereospecific biotransformation of aporphine alkaloids in Stephania epigaea to 4 R -hydroxyaporphine alkaloids by Clonostachys rogersoniana

“…It is worth noting that the Table 3 Log P values and water solubility results of aporphine alkaloids and 4R-hydroxyaporphine alkaloids. water solubilities of 1b, 2b, and 3b are 759.5 ± 36.2, 2154.1 ± 45.2, and 778.8 ± 23.7 mg/L, respectively, which are unusually higher than those of 1a, 2a, and 3a, as well as other compounds reported in the literature [16,17]. Due to these significant improvements in water solubility and bioactivities, these 4R-hydroxyaporphine alkaloids have potential as water-soluble AChE inhibitors and antitumor agents, particularly 1b and 2b.…”

“…Water solubility was measured using a previously reported method [16,17]. A total of 10.0 mg of compound was added to 1.5-mL Eppendorf tubes containing 0.5 mL of HPLC-grade water.…”

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“…As a result, the structurally similar BC48 and BC67 indicated dramatically weaker inhibitory effect against tumor cell development, and this was inferior to those demonstrated by BC80 and BC81. Lee and his colleagues investigated aqueous-soluble amine substituted analogues and discovered two novel active compounds, BC82 and BC83 in the cytotoxic activity experiment [95]. When compared to the previous compound BC67, compound BC82 had a 50 times higher aqueous solubility.…”