Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC(50) of 0.03-8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.
Background and PurposeYC‐1 exhibits potent anticancer activity via numerous actions in many cancer cell lines. Hence, we investigated the in vivo antitumour efficacy of YC‐1 in an MDA‐MB‐468 xenograft model and elucidated the mechanism of down‐regulation of enhancer of zeste homology 2 (EZH2) by YC‐1 in breast cancer cells.Experimental ApproachIn YC–1‐treated breast cancer cells and tumour specimens from YC–1‐treated MDA‐MB‐468 xenografts, EZH2 expression was analysed by Western blotting. Pharmacological inhibitors and short hairpin RNA‐mediated knockdown were applied to identify possible signalling pathways involved in EZH2 down‐regulation by YC‐1.Key ResultsYC‐1 reduced the viability of breast cancer cells and tumour growth in MDA‐MB‐468 xenografts. In breast cancer cells, YC‐1 down‐regulated EZH2 expression in a concentration‐ and time‐dependent manner. Depletion of EZH2 reduced the proliferation and susceptibility of breast cancer cells to YC–1‐induced apoptosis. EZH2 expression was suppressed in tumour specimens from YC–1‐treated MDA‐MB‐468 xenograft mice. YC‐1 enhanced both the degradation rate and ubiquitination of EZH2. The down‐regulation of EZH2 by YC‐1 was associated with activation of PKA and Src–Raf–ERK‐mediated signalling pathways. Furthermore, depletion of Casitas B‐lineage lymphoma (c‐Cbl), an E3 ubiquitin ligase, abolished YC–1‐induced apoptosis and suppression of EZH2. YC‐1 rapidly activated c‐Cbl to induce signalling associated with ERK and EZH2.Conclusion and ImplicationsWe discovered that YC‐1 induces apoptosis and inhibits tumour growth of breast cancer cells via down‐regulation of EZH2 by activating c‐Cbl and ERK. These data suggest that YC‐1 is a potential anticancer drug candidate for triple‐negative breast cancer.
New 6- (or 6,7-) substituted 2-(hydroxyl substituted phenyl)quinolin-4-one derivatives were synthesized and screened for antiproliferative effects against cancer cell lines. Structure-activity relationship correlations were established and the most promising compound 2-(3-hydroxy-5-methoxyphenyl)-6-pyrrolidin-1-ylquinolin-4-one (6h) exhibited strong inhibitory activity against various human cancer cell lines, particularly non-small cell lung cancer NCI-H522. Additional studies suggested a mechanism of action resembling that of the antimitotic drug vincristine. The presence of a C-ring OH group in 6h will allow this compound to be converted readily to a water soluble and physiochemically stable hydrophilic prodrug. Compound 6h is proposed as a new anticancer lead compound.
To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3′-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3′-methoxy moiety on the C-ring phenyl group of AN (6a–e) with 3′-hydroxy (7a–e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g–i) with a 6-hydroxy group (7g–i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above-mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis.
In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies.
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