An efficient method of thiol group introduction to the structure of common natural products and synthetic active compounds with recognized biological efficacy such genistein (1), 5,11-dimethyl-5H-indolo[2,3-b]quinolin (2), capecitabine (3), diosgenin (4), tigogenin (5), flumethasone (6), fluticasone propionate (7), ursolic acid methyl ester (8), and β-sitosterol (9) was developed. In most cases, the desired compounds were obtained easily via two-step processes involving esterification reaction employing S-trityl protected thioacetic acid and the corresponding hydoxy-derivative, followed by removal of the trityl-protecting group to obtain the final compounds. The results of our preliminary experiments forced us to change the strategy in the case of genistein (1), and the derivatization of diosgenin (4), tigogenin (5), and capecitabine (3) resulted in obtaining different compounds from those designed. Nevertheless, in all above cases we were able to obtain thiol-containing derivatives of selected biological active compounds. Moreover, a modelling study for the two-step thiolation of genistein and some of its derivatives was accomplished using the density functional theory (B3LP). A hypothesis on a possible reason for the unsuccessful deprotection of the thiolated genistein is also presented based on the semiempirical (PM7) calculations. The developed methodology gives access to new sulphur derivatives, which might find a potential therapeutic benefit.

Plant phenolic compounds have shown the ability to cooperate with one another at low doses in producing enhanced anticancer effects. This may overcome the limitations (e.g., poor bioavailability and high-dose toxicity) in developing these agents as cancer medicines. We have previously reported that the hydroxycinnamic acid derivative (HCAD) methyl-4-hydroxycinnamate and the phenolic diterpene carnosic acid (CA) can synergistically induce massive calcium-dependent apoptosis in acute myeloid leukemia (AML) at non-cytotoxic concentrations of each agent. Here, we explored the chemical nature of the synergy between HCADs and either CA, in inducing cytotoxicity, or the active metabolite of vitamin D (calcitriol), in enhancing the differentiation of AML cells. This was done by determining the structure–activity relationship of a series of hydroxycinnamic acids and their derivatives (methyl hydroxycinnamates and hydroxybenzylideneacetones) in combination with CA or calcitriol. The HCAD/CA synergy required the following critical structural elements of an HCAD molecule: (a) the para-hydroxyl on the phenolic ring, (b) the carbon C7–C8 double bond, and (c) the methyl-esterified carboxyl. Thus, the only HCADs capable of synergizing with CA were found to be methyl-4-hydroxycinnamate and methyl ferulate, which also most potently enhanced calcitriol-induced cell differentiation. Notably, the C7–C8 double bond was the major requirement for this HCAD/calcitriol cooperation. Our findings may contribute to the rational design of novel synergistically acting AML drugs based on prototype combinations of HCADs with other agents studied here.

Abstract: Novel 15N-isotope enriched potassium and diammonium thiophosphoramidates were synthesized and their spectroscopic properties, along with reactivity towards several compounds, including histidine, thymidine, glucose and 2- deoxyribose are presented. The application of quantum mechanical DFT calculations for estimation of 31P NMR chemical shifts for several thiophosphoramidate ions and its derivatives are also discussed.

All observed IR-active vibrational modes of [2,2′-bipyridyl]-3,3′-diol (BP(OH)₂) and its two isotopomers, BP(OD)₂ and BP(OH)₂-d₆ have been assigned on the basis of the comparison of experimental results with predictions obtained from DFT (B3LYP/6-31G(d,p)) calculations. The sensitivity of the vibrational transitions to the environment has been studied by comparing the spectra recorded in vapour, different solutions, KBr pellets, and cryogenic argon matrices. The results may be useful for the quantum control of excited state single or double proton transfer in BP(OH)₂.

Theoretical quantum mechanical ab initio Hartree-Fock calculations on molecular systems, modeling processes related to the specificity of thymidylate synthase inactivation are reported. We considered several steps of the methylation of the substrate dUMP and 4- or 5-mono- and 4,5-bisubstituted dUMP analogs, as well. The following reactions were modeled: the cysteine residue (Cys¹⁹⁸ in the L. casei enzyme) nucleophilic attack on the substrate and the substrate C(5)-H proton abstraction. The substrate was modeled by the 1-methyluracil molecule and its structural analogs. The cysteine Cys¹⁹⁸ residue was modeled by the methylmer-captane molecule. The substrate-enzyme binary complex was modeled by the 1-methy 1–5, 6- dihydro-6-thiomethyl-uracil (PI) molecule. The present theoretical calculations suggest that the cysteine nucleophilic attack on the substrate may result in the SH-group addition to the pyrimidine C(5)=C(6) bond in the course of a weakly exothermic reaction. The formerly presumed enolate carbanion appeared to be weakly stable or unstable and it can readily split into the thiol and pyrimidine residues. The s²-thio- (P2) and s²⁴-dithio- (P3) substrate analogs should form stable thiolate anions after cysteine residue attachment to the C(6) position of the pyrimidine ring. Studies of the deformed PI molecule interacting with a water molecule bound to the pyrimidine C(4)=0 carbonyl residue allow a suggestion that this water molecule may be directly involved in the C(5)-H proton abstraction and may serve as a proton transmitter between the substrate and the proton acceptor residue, possibly located on the cofactor N¹⁰-nitrogen. Interaction of the pyrimidine C(4)=0 group, or its modification, with the N^5,10-methylenetetrahydrofolate N(10) nitrogen atom is suggested as an additional factor influencing the inhibition process.

Density functional theory and ab–initio MP2 theoretical calculations have been employed to study the interaction between the iminodiacetate chelator, divalent metal cations, and histidine. The results of the study allow us to quantify the affinities of all divalent cations towards the iminodiacetate chelator and to suggest systems that are the best candidates for the most effective chelators. We have found that the transition-metal cations of the sixth and tenth groups are the best chelating agents. Systems with the iminodiacetate molecule loaded with either Mo, Pd, or Pt cation are predicted to strongly bind histidine and facilitate immobilization of proteins with exposed histidine residues.