A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone.

ABSTRACT: Bolinaquinone is a natural product that is a structurally complex, cytotoxic sesquiterpene quinone. A scaffold simplification and focused library approach using a microwave-assisted Suzuki coupling gave 32 bolinaquinone analogues with good-to-excellent cytotoxicity profiles. Mono-arylbenzoquinones, Library A, were preferentially toxic towards BE2-C (neuroblastoma) cells with growth inhibition (GI50) values of 4-12?µM; only the 3,4-dimethoxyphenyl 23 and 3-biphenyl 28 variants were broad-spectrum active-HT29 (colon carcinoma), U87 and SJ-G2 (glioblastoma), MCF-7 (breast carcinoma), A2780 (ovarian carcinoma), H460 (lung carcinoma), A431 (skin carcinoma), Du145 (prostate carcinoma), BE2-C (neuroblastoma), MIA (pancreatic carcinoma) and SMA (spontaneous murine astrocytoma). Library B with a second aryl moiety exhibited broad-spectrum cytotoxicity with MCF-7 cells' GI50 values of 5.6?±?0.7 and 5.1?±?0.5?µM for 2,5-dimethoxy-3-(naphthalene-1-yl)-6-(naphthalene-3-yl) 33 and 2,5-dimethoxy-3-(biaryl-2-yl)-6-(naphthalene-3-yl) 36, respectively. Similar potencies were also noted with 2,5-dimethoxy-3,6-diphenyl 30 against A2780 (GI50?=?5.9?±?0.0?µM) and with 2,5-dimethoxy-3-(biaryl-3-yl)-6-(naphthalene-3-yl) 37 against HT29 (GI50?=?5.4?±?0.4?µM), while the 3,4-dimethoxy mono-aryl analogue 23 exhibited good levels of activity against A2780 (GI50?=?3.8?±?0.75?µM), the neuroblastoma cell line BE2-C (GI50?=?3?±?0.35?µM) and SMA (GI50?=?3.9?±?0.54?µM). Introduction of the amino-substituted Library C gave 2-(naphthalen-1-yl)-5-(naphthalen-3-yl)-3,6-bis(propylamino) 43, with excellent activity against HT29 (0.08?±?0.0?µM), MCF-7 (0.17?±?0.1?µM), A2780 (0.14?±?0.1?µM), A431 (0.11?±?0.0?µM), Du145 (0.16?±?0.1?µM), BE2-C (0.08?±?0.0?µM) and MIA (0.1?±?0.0?µM).

SUBMITTER: Ghods A 

PROVIDER: S-EPMC5936891 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature