The Reaction of Dimethyltin(IV) Dichloride with Thiamine Diphosphate (H₂TDP):  Synthesis and Structure of [SnMe₂(HTDP)(H₂O)]Cl·H₂O, and Possibility of a Hitherto Unsuspected Role of the Metal Cofactor in the Mechanism of Vitamin-B₁-Dependent Enzymes

Abstract

The complex [SnMe(2)(HTDP)(H(2)O)]Cl.H(2)O, synthesized by reaction between dimethyltin(IV) dichloride and thiamine diphosphate hydrochloride (H(3)TDPCl) in water, was characterized by X-ray diffractometry and IR and Raman spectroscopy in the solid state, and by electrospray mass spectrometry (ESMS) and NMR spectroscopy ((1)H, (13)C, (31)P, (119)Sn and inverse-detection (1)H,(15)N HMBC) in aqueous solution. In the solid state the HTDP(-) anion chelates the metal via one oxygen atom of each phosphate group [Sn-O = 2.062(3), 2.292(3) A], and another oxygen atom belonging to the terminal phosphate links the SnMe(2)(2+) cations into chains. The tin atom has distorted octahedral coordination involving the trans methyl groups, the above-mentioned diphosphate oxygen atoms, and the oxygen atom of the coordinated water molecule. The thiamine moiety has F conformation. NMR studies suggest that the interaction between the organometallic cation and the HTDP(-) ligand persists in D(2)O solution, which is in keeping with the ESMS spectrum showing a peak corresponding to [SnMe(2)(HTDP)]. Both in the solid state and in solution, the acidic HTDP(-) proton in the complex is located on the N(1') atom of the pyrimidine ring. The enzymatic behavior of native pyruvate decarboxylase (EC 4.1.1.1, PDC), obtained from baker's yeast, was compared in a coupled assay with that shown by the "SnMe(2)-holoenzyme" created by incubation of apoPDC with [SnMe(2)(HTDP)(H(2)O)]Cl.H(2)O. The SnMe(2)-holoenzyme exhibited about 34% of the activity of the native enzyme (with a Michaelis-Menten constant of 2.7 microM, as against 6.4 microM for native PDC), so confirming the very low specificity of PDC regarding the identity of its metal ion cofactor. In view of the observed protonation of N(1'), it is suggested that the role of divalent cations in the mechanism of thiamine-diphosphate-dependent enzymes may be not only to anchor the cofactor in its binding site but also to shift the acidic proton of HTDP(-) from the diphosphate group to N(1'); protonation of N(1') is widely believed to be important for enzyme function, but the origin of the proton has never been clarified.

Synthesis and cytotoxic activity of dibutyltin complexes derived from pyridoxamine and salicylaldehydes

“…Among these complexes, diorganotin derivatives from pyridoxal (Casas et al, 2003;Labib et al, 1996;Nagy et al, 2008;Casas et al, 1998), pyridoxine, and thiamine (Gielen, 1996;Casas et al, 1997Casas et al, , 2000Casas et al, , 2004, belonging to vitamin B group, have attracted attention in view of their interesting activity profiles. This Electronic supplementary material The online version of this article (doi:10.1007/s00044-015-1407-8) contains supplementary material, which is available to authorized users.…”

Organo-tin antitumor compounds: Their present status in drug development and future perspectives

“…Medicinal inorganic chemistry has taken advantage of carbohydrate-appended ligands to improve solubility and molecular targeting of drug candidates [15]. Literature reports reveal that organotin(IV) moieties may bind to glycoproteins or to cellular proteins, and directly interact with DNA, causing cell death by apoptotic mechanism [16][17][18][19]. The tin-based compounds exhibit substantial binding to the phosphodiester backbone of DNA, and change the intracellular metabolism of the phospholipids of the endoplasmic reticulum [20].…”

The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss

“…Initially, organotin(IV) compounds have been analyzed against murine leukemia cell lines and also against different panels of human cancer cell lines. It was found for some studied cytotoxic compounds that the organotin(IV) moiety is bound to a phosphate group of the DNA backbone [17,18]. Importantly, organotin(IV) compounds do not develop the tumor drug tolerance that is well-established for cisplatin and its analogs [19].…”