Fine-tuning of biaryl dihedral angles: structural characterization of five homologous three-atom bridged biphenyls by X-ray crystallography

Abstract

The homologous series of three-atom bridged biaryls comprising 5,7-dihydro-1,2,3,9,10,11-hexamethoxydibenzo-[c,e]oxepine, 6,7-dihydro-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[c,e]azepinium chloride, 5,7-dihydro-1,2,3,9,10,11-hexamethoxydibenzo[c,e]thiepine, and the 6-oxide and 6,6-dioxide derivatives of the latter have been characterized by X-ray crystal structure analysis. Within this series the endocyclic and exocyclic biaryl dihedral angles vary over 10 ranges, reflecting the changing balance of intramolecular (steric, geometric) and intermolecular (crystal packing) forces, the former being potential control elements for fine-tuning the helicity of the biaryl system.

Tubulin-binding dibenz[c,e]oxepines as colchinol analogues for targeting tumour vasculature

“…The difference in potency of 40 and 51 as tubulin polymerisation inhibitors mirrors that of their respective carbocyclic analogues 71 (IC 50 > 50 mM) 48 and 72 (IC 50 1.5 mM), 49 and indicates that at least one oxygen substituent in the C-ring is a prerequisite for tubulinbinding activity. However, the hexamethoxy series comprising 63 and 66-70, which had been prepared from the diol 64 for our crystallographic study, 31 was almost devoid of activity. The cytotoxicity of the dibenzazepine 66 (entry 13) is intriguing, given that its C-ring oxygenation pattern cannot be viewed as optimal, although it is recognised that the link between cytotoxicity and the ability to inhibit tubulin polymerisation is potentially complex.…”

“…The preparative routes to the dibenzoxepines 16, 51 and 56 have also been described in a patent application. 32 Compounds 18, 34 20, 34 63 31 and 67-70 31 were prepared using published procedures.…”

“…28 The toxicity of colchicine 15 precludes its clinical use as an antimitotic agent, but it is clear that the colchicine binding site of tubulin can accommodate a diverse range of structures and so offers considerable scope for the design of binding agents with minimised pharmacokinetic halflives and cardiostimulatory effects, 29 the latter being a potentially generic problem with tubulin-targeting VDAs. 18d,30 Our interest in the axial chirality of colchicine 15 led us to analyse the variation of the interaryl dihedral angle in a series of heterocyclic variants of the bridged biaryl core, 31 and we observed that the degree of helicity in dibenz [c,e]oxepines closely matches that found in colchicine 15. In pursuing this line we synthesised a series of new dibenz [c,e]oxepines and assessed their ability to inhibit tubulin polymerisation, which led to the identification of 5,7-dihydro-3,9,10,11-tetramethoxydibenz[c,e]oxepin-4-ol 16 as a new lead in the search for effective VDAs.…”

Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents

“…1 A crystallographic analysis of the dibenz [c,e]oxepine nucleus 6 led by virtue of its ability to match, in both degree and sense, the conformational helicity of colchicine 2, which is crucial to the latter's ability to bind to tubulin, 7 and by analogy with Nacetylcolchinol methyl ether (NCME) 3, whose binding to tubulin is strong but rapidly reversible, i.e. compatible with druglike pharmacokinetics.…”

Kinetic and thermodynamic control of axial chirality in biaryl-derived fused oxazolidine lactams exploiting a centre-axis relay of unit efficiency

“…6,7 The interplay between benzylic central chirality and axis configuration, as illustrated above, is a recurrent theme in atroposelective biaryl synthesis, 1 and our interest in this area led us to investigate the potential of [7,5]-fused lactams based on 6,7dihydrodibenz[c,e]oxazolo [3,2-a]azepin-9-one 2 as conformationally restrained biaryls. Although the ring system in 2 is analogous to the [5,5]-and [6,5]-fused lactams introduced and exploited so productively by Meyers and co-workers, 8 the biaryl lactams described in our preliminary publication 9 were the first of their a School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK. E-mail: tim.wallace@manchester.ac.uk; Fax: +44 (0) 161 275 4939 b Synthetic Chemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK type.…”