Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere

Abstract

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para‐Phenyl Bioisosteres

“…[19b] In an umber of examples, moleculese ncompassing ac ubane in place of ab enzene ring weres hown to maintain similarl evels of pharmacological efficacy. [20] In these examples as light increase in lipophilicity was observed, howevert he most striking difference relates to the increased metabolic stability of the cubane derivatives. The effect on NSB of replacing p-Ph by CUB is illustrated in Figure 3w ith two pairs of molecules.…”

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…Other examples of cubane as ab ioisosteres are outlined in the publication. [74] Overall resultss howedt he applicabilityo fc ubane as ab enzene bioisostere.…”

“…While acetylene 26 is rather small with aC ÀCd istance of 1.20 , [71] the size increases gradually from BCP 4 (1.85 ), [10] to BCO 10 (2.60 ), [29] to triptycene 19 (2.61 ), [72] to cubane 37 (2.72 ), [73] which is very close to the largestrepresentative benzene 27 (2.79 ). [74] The highly strained BCP system is influencedt he mostb y electronic and steric effects. Different substituentso nt he bridgehead positions alter the internal CÀCd istance.…”

“…[62,119] Various molecules weres ynthesized to test the applicability of this hypothesis with applications in cancer therapeutics, AD medication and pain management. [74] The histoned eacetylase inhibitor SAHA 287 (suberanilohydroxamic acid), [359] used fort he treatment of cutaneous T-cell lymphoma (CTCL) was the first molecule investigated (Figure 58). Tumor cell line inhibition studies showedb oth SAHA and the cubane analogue 287 a had similarp otencies in tumorc ell inhibition, but SAHA'st oxicityw as slightly greater towardsNFF primary cells.…”

Wacker Silicone Award: A. C. Filippou / Herman Skolnik Award: D. A. Winkler / Erwin‐Schrödinger‐Preis: C. Barner‐Kowollik

“…Im Mittelpunkt seiner Forschung stehen aktuell die Vorhersage von Materialeigenschaften und die Anwendung von Methoden der Chemieinformatik auf eine Vielzahl an Materialien, darunter Nanomaterialien, biomedizinische Materialien, Keramiken, ionische und überkritische Flüssigkeiten sowie Katalysatoren. In ChemMedChem hat er einen Viewpoint‐Artikel über evolutionäre Methoden in der Wirkstoff‐Forschung veröffentlicht, und er ist Coautor einer Arbeit in der Angewandten Chemie über Bioisostere . Winkler gehört den Editorial Boards von ChemMedChem und Molecular Informatics an, und er ist der nächste Präsident der Federation of Asian Chemical Societies, die Chemistry—An Asian Journal , das Asian Journal of Organic Chemistry und ChemNanoMat unterstützt.…”