In silico approach to cisplatin toxicity. Quantum chemical studies on platinum(II)-cysteine systems.

The behaviour of cisplatin in serum, and the drastic differences between the properties of this drug and its trans-isomer were the main motivations for this work. In a search for model "thiol-platin(II)" interactions, the first steps of the following reaction systems were evaluated: (1) cisplatin-thiomethanol; (2) transplatin-thiomethanol; (3) cisplatin-cysteine; and (4) transplatin-cysteine. In each case, calculations for the associative mode of reactions were performed. The electronic structure of these molecular systems was studied at the non-empirical all-electron level using density functional theory (DFT) within the Huzinaga and WTBS basis sets including polarisation Gaussian functions and full geometry optimisation. B3LYP or EPBO density functionals were applied throughout. The calculated molecular electrostatic potentials are presented graphically. Assuming that electrostatic effects are dominant, cisplatin should interact more strongly with the sulfur atom of CH3S- and deprotonated CYS-S- than transplatin. This fact has been documented in the supermolecule model of the relevant interaction energies in both gas phase as well as within the solvent polarisable continuum model. The opposite relationship was observed when we compared values of energy differences between products and substrates for both isomers. The data obtained here could be applied to search for correlation between the biological activity of platinum complexes and their properties as estimated by various physico-chemical and in silico methodologies.

Calculation of lipophilicity for Pt(II) complexes: experimental comparison of several methods.

Platinum containing compounds are promising antitumor agents, but must enter cells before reaching their main biological target, namely DNA. Their distribution within the body, and hence their activity is to a large extent determined by their lipophilicity, thus there is a strong interest to develop computational methods to predict this important property. This study analyses accuracy of five methods, namely ALOGPS, KOWWIN, CLOGP and two quantum chemical approaches, to predict octanol/water partition coefficients (logP) for sets of 43 and 12 Pt(II) complexes, collected from the literature and measured by the authors, respectively. All methods gave generally poor results with mean absolute error (MAE) of between 0.8 and 3 log units for prediction of new compounds. Extension of the ALOGPS program with data from the literature set resulted in the best prediction ability, MAE=0.46, for the measured molecules. The program was also able to correctly predict errors in calculated logP values. It is freely available for interactive use at http://www.vcclab.org.

Antiproliferative activity of vitamin D compounds in combination with cytostatics.

Calcitriol is a potent antiproliferative agent against various tumour cells in vitro. Here, the results of a study on vitamin D compounds (calcitriol's analogues PRI-1906 and PRI-2191) as potential agents in combined antitumour therapy in vitro are presented. Applying antiproliferative SRB and MTT assays, the growth inhibitory effects of the vitamin D compounds, applied alone or in combination with either cisplatin or doxorubicin, were measured. The following cancer cell lines were employed: A549 (human non-small cell lung carcinoma), B16 (murine melanoma), CCRF, HL-60 (human leukaemia), SW707 (human colon cancer), MCF-7, T47D (human breast cancer), WEHI-3 (mouse leukaemia) and normal cells: BALB 3T3 (normal murine fibroblast cell line). It was shown that the treatment of tumour cells, which are sensitive to vitamin D compounds, with the combination of vitamin D compounds and cytostatics decreased the inhibitory concentration 50% (IC50) values compared with the effects of the cytostatics applied alone.

Synthesis and antiproliferative activity of some 5-substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles.

A series of new 5-substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles has been synthesised and evaluated for their antiproliferative activity. The compounds were prepared by the reaction of the sulphinylbis(2,4-dihydroxythiobenzoyl) (STB) wit hydrazides or carbazates. The panel substitution included alkyl, alkoxy, aryl and heteroaryl derivatives. The structures of compounds were identified from the elemental, IR, (1)H NMR and MS spectra analysis. The highest antiproliferative activity against the cells of human cancer lines for 2-(2,4-dihydroxyphenyl)-5-(4-methoxybenzyloxy)-1,3,4-thiadiazole was found with ID(50) values comparable (HCV29T and SW707) or significantly lower (T47D) than for cisplatin applied as the reference compound. The influence of 5-substiution type of 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles on antiproliferative activity is discussed.

Synthesis and in vitro antileukemic activity of some new 1,3-(oxytetraethylenoxy)cyclotriphosphazene derivatives.

A new series of 1,3-(oxytetraethylenoxy)cyclotriphosphazene derivatives bearing 2-chloroethylamine or salicylaldehyde (2-hydroxybenzaldehyde) or its Schiff base (after condensation with 2-chloroethylamine) units and having also 2-naphthyl or anthraquinone groups as cosubstituents has been synthesized. The in vitro cytotoxic activity of these compounds against a panel of four cancer cell lines has been studied. Most of the compounds exhibited antiproliferative activity in the range of the international criterion for synthetic agents (4 microg/mL) against the MOLT4, L 1210, HL-60, and P388 cell lines chosen for testing.

Correlation between VDR expression and antiproliferative activity of vitamin D3 compounds in combination with cytostatics.

Calcitriol is a potent antiproliferative agent against various tumour cells in vitro. Its biological activity is mediated by the vitamin D receptors (VDRs). Here, we present the results of a study on vitamin D3 compounds (calcitriol and its analogue PRI-2191) as potential agents in combined antitumour therapy in vitro. Applying antiproliferative SRB and MTT assays, we measured the growth inhibitory effects of vitamin D compounds applied alone or in combination with either cisplatin or doxorubicin. Next, we examined the correlation of this effect with the presence of nVDR (nuclear VDR). The following cancer cell lines were applied: HL-60 (human leukaemia), SW707 (human colon cancer), A549 (human lung cancer), WEHI-3 (mouse leukaemia). The treatment of tumour cells with the combination of vitamin D compounds and cytostatics decreased the inhibitory concentration 50% (IC50) values compared with the effects of cytostatics applied alone. The synergistic effect was positively correlated with nVDR expression.

[Biological activity of calcitriol and its new analogues -- potential therapeutic applications]. / Wlasciwosci biologiczne kalcytriolu i jego nowych analogów - potencjalne zastosowania terapeutyczne.

Calcitriol is effective not only in the regulation of calcium-phosphate homeostasis, but also in promoting the differentiation and inhibition of proliferation of various cells. Calcitriol seems to be a potent drug with various therapeutic applications, such as regulation of calcium-phosphate homeostasis and treatment of psoriasis, autoimmune diseases, and cancer. Since clinical use of calcitriol is largely limited, due to its undesirable side effect of hypercalcemia, numerous calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. This paper summarizes the current state of knowledge concerning the cellular mechanisms of calcitriol's biological activity and their clinical implications. Such medical application includes treatment (as a single-drug or in combination) of osteoporosis, renal osteodystrophy, psoriasis (calcipotriol or tacalcitol ointment), autoimmunological diseases (including multiple sclerosis), and some cancers. The efforts to obtain new vitamin D3 analogues are also briefly reviewed. The structures and roles of vitamin D receptors in the biological effects of calcitriol and its analogues are discussed.

Synthesis and in vitro cytostatic activity of some new 1,3-(oxytetraethylenoxy)-cyclotriphosphazatriene derivatives.

A series of cyclophosphazene crown ether derivatives bearing aziridinyl (ethylene imine) units and also 2-naphthyl or anthraquinone groups as co-substituents has been synthesized and their cytostatic activity against the panel of eight cancer cells in vitro has been studied. The substituents used exhibit different activities: alkylation (aziridinyl groups) and intercalation (naphtyl, anthraquinone groups) against DNA. These both interactions are supposed to enhance the efficiency of the cyclophosphazene crown ether derivatives studied as cytotoxic agents.

Synthesis, structure, and cytostatic properties of new olivacine derivatives.

Starting from 2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethylamine and 6-methylpicolinic acid, 9-methoxy-5-methyl-1-(6-methylpyridin-2-yl)-6H-pyrido[4,3-b]carbazole 10 and its 6-alkylderivatives 12-17 were obtained. The newly obtained compounds showed significant cytostatic activity against cultured L1210 cells and high cytotoxicity towards various human tumor cell lines.