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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

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

Ghods Azadeh A Gilbert Jayne J Baker Jennifer R JR Russell Cecilia C CC Sakoff Jennette A JA McCluskey Adam A

Royal Society open science 20180404 4

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< ...[more]

PMID: 29765626

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Project description:Health organizations worldwide have warned that we are on the cusp of a "post-antibiotic era," necessitating new approaches to combat antibiotic resistant infections. One such approach is the development of antibiotic adjuvants, which have little or no inherent antibiotic activity at their active concentrations but instead potentiate the activity of antibiotics against antibiotic-resistant bacteria. Recently, we demonstrated that meridianin D, a natural product originally reported to have activity against Staphylococcus aureus and Mycobacterium tuberculosis, possesses the ability to reverse colistin resistance in colistin resistant bacteria. As most natural product screens typically involve screening for only certain activities (anticancer, antiviral, and antimicrobial are typical), we posited that the meridianin D discovery was not unique and there are potentially many natural products that have adjuvant activity. To explore this, the National Cancer Institute (NCI) Natural Product Library Set IV was screened for adjuvant activity using four classes of antibiotics (β-lactams, aminoglycosides, macrolides, and polymyxins) against three bacterial pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Klebsiella pneumoniae). Sixteen compounds suppressed β-lactam resistance in MRSA, five of which effected a 16-fold reduction in the oxacillin minimum inhibitory concentration (MIC). Two natural products effectively suppressed aminoglycoside resistance in both of the Gram-negative species tested, and no hits were observed with macrolides. In contrast, a larger number of natural product adjuvants were identified when screening against colistin-resistant strains of A. baumannii and K. pneumoniae. Nine compounds reduced the colistin MIC to its breakpoint or lower (up to a 1024-fold reduction). Clorobiocin, novobiocin, and prodigiosin were most effective, reducing the colistin MIC in K. pneumoniae strain B9 to 2 μg/mL at concentrations as low as 0.625, 2.5, and 1.25 μM, respectively. Restored sensitivity to colistin with these compounds does not appear to coincide with known mechanisms of colistin resistance.

Dataset Information

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

Publications

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

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