WILLIAM FENICAL

Professor

Center for Marine Biotechnology & Biomedicine

Distinguished Professor of Oceanography

Research Interests

Chemistry of marine plants, microorganisms and invertebrate animals.
Utilization of marine-derived compounds for the treatment of various human diseases, in particular cancer and infectious diseases.

Degrees

B.S., California State Polytechnic University
M.S., San Jose State University
Ph.D., University of California, Riverside

Recent Publications

Hammons, JC, Trzoss L, Jimenez PC, Hirata AS, Costa-Lotufo LV, La Clair JJ, Fenical W. 2019. Advance of seriniquinone analogues as melanoma agents. Acs Medicinal Chemistry Letters. 10:186-190. AbstractWebsite

Seriniquinone, a marine natural product, displayed potent cytotoxicity and selectivity against melanoma cancer cells. This selectivity, combined with a novel mode of action (MOA), prompted studies to translate a pharmacologically relevant lead. Herein, we report on structure-activity relationships (SARs), and provide a strategy to prepare analogues that retain activity and offer an improved water solubility and isomeric purity. From intermediates made on a gram-scale, derivatives were prepared and evaluated for their antiproliferation activity and melanoma selectivity. Overall these studies provide methods to install side chain motifs that demonstrate a common, and yet unique, biological profile.

Le, TC, Lee EJ, Lee J, Hong A, Yim CY, Yang I, Choi H, Chin J, Cho SJ, Ko J, Hwang H, Nam SJ, Fenical W. 2019. Saccharoquinoline, a cytotoxic alkaloidal meroterpenoid from marine-derived bacterium Saccharomonospora sp. Marine Drugs. 17 AbstractWebsite

A cytotoxic alkaloidal meroterpenoid, saccharoquinoline (1), has been isolated from the fermentation broth of the marine-derived bacterium Saccharomonospora sp. CNQ-490. The planar structure of 1 was elucidated by 1D, 2D NMR, and MS spectroscopic data analyzes, while the relative configuration of 1 was defined through the interpretation of NOE spectroscopic data. Saccharoquinoline (1) is composed of a drimane-type sesquiterpene unit in combination with an apparent 6,7,8-trihydroxyquinoline-2-carboxylic acid. This combination of biosynthetic pathways was observed for the first time in natural microbial products. Saccharoquinoline (1) was found to have cytotoxicity against the HCT-116 cancer cell line by inducing G1 arrest, which leads to cell growth inhibition.

Shang, Z, Winter JM, Kauffman CA, Yang I, Fenical W. 2019. Salinipeptins: Integrated genomic and chemical approaches reveal unusual D-amino acid-containing ribosomally synthesized and post-translationally modified peptides (RiPPs) from a Great Salt Lake Streptomyces sp. Acs Chemical Biology. 14:415-425. AbstractWebsite

Analysis of the full genome of an environmentally unique, halotolerant Streptomyces sp. strain GSL-6C, isolated from the Great Salt Lake, revealed a gene cluster encoding the biosynthesis of the salinipeptins, D-amino-acid containing members of the rare linaridin subfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). The sequence organization of the unmodified amino acid residues in salinipeptins A D (1-4) were suggested by genome annotation, and subsequently, their sequence and post-translational modifications were defined using a range of spectroscopic techniques and chemical derivatization approaches. The salinipeptins are unprecedented linaridins bearing nine D-amino acids, which are uncommon in RiPP natural products and are the first reported in the linaridin subfamily. Whole genome mining of GSL-6C did not reveal any homologues of the reported genes responsible for amino acid epimerization in RiPPs, inferring new epimerases may be involved in the conversion of L- to D-amino acids. In addition, the N-oxide and dimethylimidazolidin-4-one moieties in salinipeptins B and C, which are modified from N,N-dimethylalanine, are unknown in bacterial peptides. The three-dimensional structure of salinipeptin A, possessing four loops generated by significant hydrogen bonding, was established on the basis of observed nuclear Overhauser effect (NOE) correlations. This study demonstrates that integration of genomic information early in chemical analysis significantly facilitates the discovery and structure characterization of novel microbial secondary metabolites.

Nakatsuji, T, Chen TH, Butcher AM, Trzoss LL, Nam SJ, Shirakawa KT, Zhou W, Oh J, Otto M, Fenical W, Gallo RL. 2018. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Science Advances. 4 AbstractWebsite

We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine ( 6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6-HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense.

da Silva, RM, Guaratini T, Jimenez PC, Fenical W, Costa-Lotufo LV, Vessecchi R, Lopes NP. 2018. Mass spectrometry analysis of protonated marine natural product seriniquinone. Journal of the Brazilian Chemical Society. 29:1162-1166. AbstractWebsite

Seriniquinone is a natural quinone isolated from a rare marine bacterium of the genus Serinicoccus. This secondary metabolite has been shown to have anticancer properties, which has raised attention of the scientific community. In this short report, we present the first investigation of the gas-phase chemistry fragmentation reactions of seriniquinone in electrospray ionization tandem mass spectrometry (ESI-MS/MS), to be further applied in pharmacokinetics and metabolism studies. All the proposals herein were supported by computational chemistry.