ChemInform Abstract: A Novel Palladium‐Mediated Coupling Approach to 2,3‐Disubstituted Benzo[b]thiophenes and Its Application to the Synthesis of Tubulin Binding Agents.

Abstract

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of a 3-(α-Styryl)benzo[b]-thiophene Library via Bromocyclization of Alkynes and Palladium-Catalyzed Tosylhydrazones Cross-Couplings: Evaluation as Antitubulin Agents

“…Although the synthesis of 2,3-disubstituted benzothiophenes is well documented, to our knowledge, only one report deals with the synthesis of 2-aryl-3-(α-styryl)benzothiophenes through a Wittig reaction . We have recently shown that the electrophilic cyclization of 2-(1-alkynyl)thioanisoles in the presence of N -methylpyrrolidin-2-one hydrotribromide (MPHT) provides a mild, high yielding synthesis of 3-bromo-benzothiophenes .…”

Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties

“…X-ray crystal structure analysis of 10 revealed the A-ring to be rotated toward the D-ring in a pseudo-π-stacking arrangement . It was concluded that this conformation is likely to be important to binding, and early SAR studies within our group indicated that the A- and D-rings of 10 may coincide with the A- and B-rings of 4 . − For example, the introduction of a 3′-hydroxyl to the D-ring of 10 (compound 11 ) increased structural analogy to 4 and increased potency (entry 3, Table ). Also, removal of the B-ring in 11 was well tolerated, giving an even more potent compound 14 (entry 4, Table ).…”

“… a Inhibition of extent of microtubule assembly was the parameter measured. b All data were obtained from the same laboratory: refs − . c The rate but not the extent of tubulin polymerization was inhibited by 50%. …”

“…Thus, the B-ring in I / II plays an equivalent role to the B-ring in 4 and the presence of a C2-aryl does not influence this conformation. This is also consistent with our earlier observation that a C6-methoxy is required for the potency of I (X = S), even when a C2-aryl is present . An alternative explanation for the increase in potency of 11 relative to 10 (entries 2 and 3, Table ) may be that the inhibitory effects of 10 are limited by poor solubility at higher assay concentrations and that the presence of a hydroxyl in 11 improves solubility.…”

“…On the other hand, we also found that small changes in the substitution pattern of the B-ring of 10, such as removal or relocation of the C6methoxy to C5, completely eliminated activity, indicating that the B-ring does contribute to activity when present (data not shown). 19 We also identified that the benzo [b]furan 12 and indole 13 analogues of benzo [b]thiophene 11 were much more potent (compare entries 3, 5, and 6, Table 1) and that for all systems I (X = O, S, NH) the carbonyl linker between the A-and C-rings is essential for activity (data not shown). 21,22 Later, Hseih 2 and Scheme 1).…”