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

• Published in: Journal of chemical crystallography 2016-02, Vol.46 (2), p.105-112
• Main Authors: Gerova, Mariana S., Encheva, Gergina R., Nikolova, Rositsa P., Chanev, Christo D., Shivachev, Boris L., Apostolova, Margarita D., Petrov, Ognyan I.
• Format: Article
• Language: English
• Subjects: Chemistry; Chemistry and Materials Science; Crystallography and Scattering Methods; Inorganic Chemistry; Organometallic Chemistry; Original Paper; Physical Chemistry
• ISSN: 1074-1542; 1572-8854
• DOI: 10.1007/s10870-016-0633-3

( 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, 1 H and 13 C 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 P 2 1 / 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 IC 50 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.