2:1 Adduct of colchiceine acetate and ethyl acetate

Abstract

C23H25NO7.½C4HsO2, M r = 471.49, is orthorhombic, P212121, with a = 9.299 (3), b = 10.534 (4), c = 27.084 (6) A, V = 2653 (4) A 3, z = 4, 2(Mo Ka) = 0.71069 A, D c = 1.180, D m --1.16 (2) Mg m -3. The structure was solved by the Patterson search approach where the molecular structure of isocolchicine was used as the search model and refined by full-matrix leastsquares methods. The final R value was 0.077 for 1552 observed reflections. The ethyl acetate molecule shows an occupation factor of 0.5, and the acetamido O atom is disordered. The position of the acetoxy group in the solid state defines the molecule as belonging to the isocolchicine series. The conformation of colchiceine acetate may explain its lack of accessibility at the tubulin binding site and therefore its decreased biological activity. IntroductionColchicine, C22H25NO6, is an alkaloid extracted from the meadow saffron or autumn crocus (Colehieum autumnale L.) and other Liliaeeae. It presents a large number of biological effects, but the most important of these is doubtless its inhibiting action in the process of mitosis, believed to result from the specific strong binding of colchicine to tubulin. This process interferes with the assembly of this protein into the microtubules of the mitotic spindle. Thus, colchicine and some of its derivatives which bind well to tubulin behave as * Present address: Departamento de Cristalografia, Universidad de Barcelona, Spain.5" Research associate of the National Foundation for Scientific Research (Belgium).0567-7408/82/061782-05501.00 powerful antimitotics and therefore have potential antitumor activity.In order to try to clarify the relationships between structure and biological activity in the products of the colchicine series the crystal structures of colchicine (I) (R = CH3) (Lessinger & Margulis, 1978a), its inactive isomer, isocolchicine (II) (R = CH3) (Lessinger & Margulis, 1978b), and other derivatives (Margulis, 1974(Margulis, , 1977Koerntgen & Margulis, 1977;Clark & Margulis, 1980; Brossi, R6sner, Silverton, Iorio & Hufford, 1980;Margulis & Lessinger, 1978;Margulis, 1975; Silverton, 1979) have recently been determined. On the other hand, Blad6-Font (1977a,b, 1978 has synthesized some new derivatives of colchicine with the same aim in view. Among these the crystal structure of the O,N-diacetate of the enolic form of colchicine was solved (Busetta, Leroy, Hospital, Elguero & Blad6-Font, 1979).( .}; \<c...Structural variations of colchicine have shown that the arrangement of the tropolone ether function is critical, isocolchicine derivatives of the general formula (II) being considerably less active biologically (R6sner, Caparo, Jacobson, Atwell, Brossi, Iorio, Williams, Sik & Chignell, 1981; Santav3), 1979). In this connection we deemed it of interest to determine by X-ray diffraction the crystal structure of colchiceine acetate (II) (R = COCH3) to contribute toward the understanding of the specific interactions of colchicine © 1982 International Union of Crystallography MIRAVITLLES, SOLAN...

Antifungal, anticancer, and docking studies of colchiceine complexes with monovalent metal cation salts

“…To evaluate antifungal potency of prepared complexes, they were subjected tests against eight pathogenic fungi commonly known as mold ( Table 2, Table 3). The salts used for preparation of complexes exhibited no activity against fungi strains (Table S2), whereas (Miravitlles et al, 1982).…”

“…Although much biological information has been published about colchiceine, not much attention has been paid up to now on the formation of complexes between colchiceine and monovalent metal cation salts and their biological relevance. In earlier works, the crystal structures of colchiceine ethyl acetate‐water solvate (Silverton, ) and colchiceine adduct with acetate and ethyl acetate (Miravitlles, Solans, Bladѐ‐Font, Germain, & Declero, ) have been reported. The only one known complex of colchiceine in the crystal is that with Cu 2+ metal cation (Mackay, Gable, Morrison, & Satzke, ).…”