A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone - PubMed (original) (raw)

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

Azadeh Ghods et al. R Soc Open Sci. 2018.

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).

Keywords: Suzuki coupling; bolinaquinone; cytotoxicity; microwave-assisted synthesis.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.

Figure 1.

The chemical structures of selected sesquiterpene quinones: bolinaquinone (1), avarone (2), mamanuthaquinone (3), epi-ilimaquinone (4), nakijiquinone A (5), dysidaminone E-5 (6) and 18-phenethylaminoavarone (7), and their reported cytotoxicity towards different cancer cell lines.

Figure 2.

Figure 2.

The proposed structural simplification of the lead, bolinaquinone 1, to afford three bolinaquinone libraries: A, B and C.

Scheme 1.

Scheme 1.

Reagents and conditions: (i) MeOH, H2SO4, 25°C, 6 h; (ii) NBS, DMF, 60°C (then 25°C), 5–8 h; (iii) arylboronic acid (Ar-B(OH)2), Pd(dppf)Cl2, K2CO3, dioxane, µW, 120°C, 20 min, or arylboronic acid (R-B(OH)2), Pd(dppf)Cl2, K2CO3, toluene, reflux, 72 h.

Scheme 2.

Scheme 2.

Reagents and conditions: (i) 2 equivalents of arylboronic acid (R-B(OH)2), Pd(dppf)Cl2, K2CO3, dioxane, μW, 120°C, 20 min; (ii) 1 equivalent of arylboronic acid (R-B(OH)2), Pd(dppf)Cl2, K2CO3, dioxane, μW, 120°C, 20 min, then 1 equivalent of arylboronic acid (R'-B(OH)2), 120°C, 20 min.

Scheme 3.

Scheme 3.

Reagent and conditions: (i) _n_-propyl amine or _N,N_-dimethylpropane-1,3-diamine, MeOH, 25°C, 1 h.

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References

    1. AIHW & AACR. 2012. Cancer in Australia: an overview. 2012 Cancer series no. 74. Cat. no. CAN 70. Canberra, Australia: AIHW.
    1. Joshi S, et al. 2010. The dynamin inhibitors MiTMAB and OcTMAB induce cytokinesis failure and inhibit cell proliferation in human cancer cells. Mol. Cancer Ther. 9, 995–2006. (doi:10.1158/1535-7163.MCT-10-0161) - DOI - PubMed
    1. Chircop M, et al. 2011. Inhibition of dynamin by dynole 34–2 induces cell death following cytokinesis failure in cancer cells. Mol. Cancer Ther. 10, 1553–1562. (doi:10.1158/1535-7163.MCT-11-0067) - DOI - PubMed
    1. Smith CM, Haucke V, McCluskey A, Robinson PJ, Chircop M. 2013. Inhibition of clathrin by Pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells. Mol. Cancer 12, 4 (doi:10.1186/1476-4598-12-4) - DOI - PMC - PubMed
    1. Hill TA, Stewart SG, Gordon CP, Ackland SP, Gilbert J, Sauer B, Sakoff JA, McCluskey A. 2008. Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition. ChemMedChem. 3, 1878–1892. (doi:10.1002/cmdc.200800192) - DOI - PubMed

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