Synthesis, crystal structure from PXRD of a Mn^II(purp)₂complex, interaction with DNA at different temperatures and pH and lack of stimulated ROS formation by the complex

Abstract

The formation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for its antitumor activity but they also make these drugs cardiotoxic. When complexed with metal ions there is a decrease in ROS formation and therefore in cardiotoxicity. Interestingly, inspite of producing fewer ROS, some of the complexes are effective antitumor agents, often better than the parent anthracycline. Purpurin (LH 3 ), a hydroxy-9, 10-anthraquinone, resembles doxorubicin at the core. An Mn II complex of LH 3 [Mn II (LH 2 ) 2 ] was synthesized to see the extent to which the complex resembles metal-anthracyclines with regard to structure and function. Crystal structure was determined by Rietveld refinement of PXRD data using an appropriate structural model developed on the basis of spectroscopic information. This being only the second report on the crystal structure of a hydroxy-9,10-anthraquinone with a 3d-transition metal ion. Bond lengths, bond angles were obtained by structural refinement.The structure is supported by DFT calculations. DNA binding of the complex is slightly better than purpurin but more importantly unlike purpurin, the binding constant values remained constant even with an increase in the pH of the medium. The NADH dehydrogenase assay and the DCFDA-ROS generation assay showed that generation of superoxide in the former and ROS in general in the latter were significantly less for the complex than for purpurin. Even with decreased ROS formation, the complex is able to maintain the biological activity of purpurin. occurs through sequential one-electron transfer steps, generating Mn(III) intermediates. [45][46][47] . Thus for this study, an Mn(II) complex of 1,2,4-trihydroxy-9,10-anthraquinone (purpurin) was prepared and some of its parameters compared with known metal complexes of anthracyclines or hydroxy-9,10anthraquinones. 12,14,15,[20][21][22][23] Purpurin (1, 2, 4 trihydroxy-9,10-anthraquinone) resembling the core of anthracyclinesThe novel aspects of this study are the structure of the complex obtained from powder X-ray diffraction data since single crystals were not obtained, determination of thermodynamic parameters pertaining to interaction of purpurin and its complex with calf thymus DNA and lack of stimulated ROS formation by the complex. The structure is novel since the same is rare for metal complexes of hydroxy-9,10-anthraquinones, with only one report so far from single crystal X-ray diffraction. 48 This is only the second structure of a metal complex of a hydroxy-9,10-anthraquinone with a 3d transition metal ion. 14 The importance of the thermodynamic study is that it helps to explain trends observed in binding of a hydroxy-9,10-anthraquinone and its metal complex with DNA that puts our results in proper perspective with that of established anthracyclines and their metal complexes. Decrease in ROS generation by the complex is important for it indicates that the complex is likely to be less cardiotoxic.

Activity of CoII–Quinalizarin: A Novel Analogue of Anthracycline-Based Anticancer Agents Targets Human DNA Topoisomerase, Whereas Quinalizarin Itself Acts via Formation of Semiquinone on Acute Lymphoblastic Leukemia MOLT-4 and HCT 116 Cells

“…40 Through previous work, we reported three structures of metal complexes of hydroxy-9,10-anthraquinones (purpurin and emodin) from powder diffraction data. 10,41,42 Attempts were made to obtain single crystals of the Co II complex as well but we were not successful. We tried obtaining the structure from powder diffraction data but failed.…”

A ZnIIcomplex of ornidazole with decreased nitro radical anions that is still highly active onEntamoeba histolytica

“…[12][13][14][15] Hence, generating the correct amount or making it available through slow chemical release is becoming an important aspect of research. [10][11][12][13][14][15] This study reports the regulation of R-NO 2 c À for a specic cause, and this is achieved through the complex formation of one of the members of the 5-nitroimidazole family (ornidazole) with Zn II , which can likely generate the correct amount necessary for cytotoxicity of a biological target (axenic Entamoeba histolytica). In addition, what the drug compromises for by forming less free radical species, (R-NO 2 c À ), it makes up for by other attributes of complex formation.…”

Facile total synthesis of lysicamine and the anticancer activities of the RuII, RhIII, MnII and ZnII complexes of lysicamine

“…Among thousands of candidates, three ruthenium complexes, i.e ., [ImH] [ trans -RuCl 4 (DMSO)Im] (NAMI-A) [ 19 ], [ImH] [ trans -RuCl 4 Im 2 ] (KP1019) [ 20 ], and Na[ trans -RuCl 4 Im 2 ] (NKP-1339 or IT-139) [ 21 ] are currently tested in clinical trials as anticancer drugs. Besides, the complexes of Rh(III) [ 22 – 26 ], Zn(II) [ 27 – 29 ], and Mn(II) [ 30 , 31 ] with potential antitumor activity have also been reported.…”