Synthesis, Crystal Structure and Cytotoxic Properties of Nitrocombretastatins (E)- and (Z)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene

Abstract

(Z)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene (2) is the key intermediate for the preparation of several anticancer agents, belonging to the group of aminocombretastatins (AC7739, AVE8062). Synthesis of the title compounds was achieved by a modified Wittig reaction under Boden’s conditions using potassium carbonate as a base and 18-crown-6 as a phase transfer catalyst. Both π-diastereoisomers were characterized by single crystal X-ray diffraction analysis, ¹H and ¹³C NMR spectroscopy. (E)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene (1) crystallizes in the orthorhombic space group Pbca (N° 61) with one molecule per asymmetric unit while (Z)-5-(4-methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene (2) crystallizes in the monoclinic space group P2₁/c (N° 14) also with one molecule per asymmetric unit. In both compounds no typical hydrogen bonding interactions could be located. The three-dimensional crystal structure is stabilized by C–H···O interactions. The cytotoxicity of synthesized nitrocombretastatins was also evaluated. The Z-stilbene 2 inhibited cell growth with IC₅₀ of 0.15 and 0.11 µM following 72 h treatment in EA.hy926 and MG-63 cell lines.

Graphical Abstract

Synthesis, crystal structure and cytotoxic properties of two stilbene derivatives (E)- and (Z)-5-(4-methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene are reported. The compounds can be examined as precursors for the synthesis of combretastatin A-4 analogues.