The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement

• Published in: Organic & biomolecular chemistry Vol. 17; no. 28; pp. 679 - 6798
• Main Authors: Houston, Sevan D, Fahrenhorst-Jones, Tyler, Xing, Hui, Chalmers, Benjamin A, Sykes, Melissa L, Stok, Jeanette E, Farfan Soto, Clementina, Burns, Jed M, Bernhardt, Paul V, De Voss, James J, Boyle, Glen M, Smith, Maree T, Tsanaktsidis, John, Savage, G. Paul, Avery, Vicky M, Williams, Craig M
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 17.07.2019; Royal Society of Chemistry
• Subjects: Agrochemicals; Antibiotics; Anticancer properties; Antihistamines; Antineoplastic Agents - chemistry; Antitumor activity; Benzene; Benzene - chemistry; Benznidazole; Benzoates - chemistry; Biocompatibility; Biological activity; Cancer; Cefaclor; Chagas' disease; Chemistry; Chemistry, Organic; Complement; Crystallography; Cubane; Cyclooctanes - chemistry; Diphenhydramine; Ketamine; Molecular Structure; Muscle relaxants; Muscles; Nitroimidazoles - chemistry; Penicillin; Physical Sciences; Science & Technology; Smooth muscle; Tetrahydronaphthalenes - chemistry; Triflumuron; Vector-borne diseases; MEDICINAL CHEMISTRY; FUNCTIONALIZATION; MECHANISM; NUCLEUS; SYSTEMATIC SUBSTITUTION; SOLUBILITY; KETAMINE
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c9ob01238a

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations ( e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement. Trials and tribulations of the cubane paradigm in biomolecule discovery highlight synthetic limitations, culminating in a continuing guide for practitioners, which includes cyclooctatetraene.