: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

Antitumour metal compounds: more than theme and variations

The immune system deploys a multitude of innate and adaptive mechanisms not only to ward off pathogens but also to prevent malignant transformation ("immune surveillance"). Hence, a clinically apparent tumor already reflects selection for those malignant cell clones capable of evading immune recognition ("immune evasion"). Metal drugs, besides their well-investigated cytotoxic anticancer effects, massively interact with the cancer-immune interface and can reverse important aspects of immune evasion. This topic has recently gained intense attention based on combination approaches with anticancer immunotherapy (e.g., immune checkpoint inhibitors), a strategy recently delivering first exciting results in clinical settings. This review summarizes the promising but still extremely fragmentary knowledge on the interplay of metal drugs with the fidelity of anticancer immune responses but also their role in adverse effects. It highlights that, at least in some cases, metal drugs can induce long-lasting anticancer immune responses. Important steps in this process comprise altered visibility and susceptibility of cancer cells toward innate and adaptive immunity, as well as direct impacts on immune cell populations and the tumor microenvironment. On the basis of the gathered information, we suggest initiating joint multidisciplinary programs to implement comprehensive immune analyses into strategies to develop novel and smart anticancer metal compounds.

Metal Drugs and the Anticancer Immune Response.

Ascorbate (Asc) reductions of the oral anticancer platinum(IV) prodrugs cis,trans,cis-[PtCl2(OAc)2(cha)(NH3)] (JM216) and cis,trans,cis-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)] (JM394) and trans,trans,trans-[PtCl2(OAc)2(cha)(NH3)] (JM576) (OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to cis-[PtCl2(cha)(NH3)] (JM118) and JM394 and 576 to cis- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: −d[Pt(IV)]/dt = k [Pt(IV)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2−] + [HAsc−] + [H2Asc]. Reduction of JM216 and JM221 is slow (overall rate constants k298 = 5.08 ± 10−2 and 3.25 × 10−2 mol−1 dm3 s−1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster (k298 = 230 ± 6 mol−1 dm3 s−1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2− and less efficiently by HAsc− leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc− and Asc2− at 25 °C are 0.548 ± 0.004 and (4.46 ± 0.01) × 106 mol−1 dm3 s−1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2− at 25 °C are calculated to be 672 ± 15 and 428 ± 10 mol−1 dm3 s−1, respectively and reduction by HAsc− was not observed under these conditions. Thus, Asc2− is up to 7 orders of magnitude more efficient as a reductant than HAsc−. H2Asc is virtually inactive. The activation parameters ΔH‡ and ΔS‡ for reduction of JM216, JM221, JM394, and JM576 by Asc2− are 52 ± 1, 46 ± 1, 56.2 ± 0.5, and 63 ± 2 kJ mol−1 and −97 ± 4, −120 ± 4, −24 ± 2, and −8 ± 5 J K−1 mol−1, respectively. An isokinetic relationship gives further support to the mechanistic assignments.

Kinetics and mechanism for reduction of oral anticancer platinum(IV) dicarboxylate compounds by L-ascorbate ions

New monofunctional platinum(II) and palladium(II) complexes: Studies of the nucleophilic substitution reactions, DNA/BSA interaction, and cytotoxic activity.

In the present study, cytotoxic effects of cisplatin, the most usually used chemotherapeutic agent, were compared with new designed platinum(IV) ([PtCl4(en)] (en = ethylenediamine) and [PtCl4(dach)]) (dach = (±)-trans-1,2-diaminocyclohexane) and platinum(II) complexes ([{trans-Pt(NH3)2Cl}2(μ-pyrazine)](ClO4)2 (Pt1), [{trans-Pt(NH3)2Cl}2(μ-4,4'-bipyridyl)](ClO4)2DMF(Pt2),[{trans-Pt(NH3)2Cl}2(μ-1,2-bis(4pyridyl)ethane)](ClO4)2 (Pt3)), in vitro and in vivo against human and murine lung cancer cells, to determine anti-tumor potential of newly synthesized platinum-based drugs in the therapy of lung cancer. Results obtained by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], Lactate dehydrogenase and Annexin V/Propidium Iodide assays showed that, among all tested complexes, [PtCl4(en)] had the highest cytotoxicity against human and murine lung carcinoma cells in vitro. [PtCl4(en)] showed significantly higher cytotoxicity then cisplatin in all tested concentrations, mainly by inducing apoptosis in lung cancer cells. [PtCl4(en)] was well tolerated in vivo. Clinical signs of [PtCl4(en)]-induced toxicity, such as changes in food, water consumption or body weight, nephrotoxicity or hepatotoxicity was not observed in [PtCl4(en)]-treated mice. [PtCl4(en)] managed to increase presence of CD45+ leukocytes, including F4/80+ macrophages, CD11c+ dendritic cells, CD4+ helper and CD8+ cytotoxic T cells (CTLs) in the lungs, cytotoxic NK, NKT and CTLs in the spleens of tumor bearing mice, resulting with reduction of metastatic lesions in the lungs, indicating its potential to stimulate anti-tumor immune response in vivo. Due to its anti-tumor cytotoxicity, biocompatibility, and potential for stimulation of anti-tumor immune response, [PtCl4(en)] may be a good candidate for further testing in the field of medicinal chemistry.

In vitro and in vivo anti-tumor effects of selected platinum(IV) and dinuclear platinum(II) complexes against lung cancer cells

Mechanistic insight on the chemistry of potential Pt antitumor agents as revealed by collaborative research performed in Kragujevac and Erlangen

The alleles and genotypes at the locus αS1 - casein were determined for 98 goats of domestic Balkan goat breed from Montenegro distributed in two flocks. The occurrence of two alleles (A and F) and three genotype forms (AA, AF and FF) were discovered by using the method of sequencing of cDNA and part of genomic DNA of αS1 casein. High domination of the strong A allele (0.629) in comparison with the 'weak' F allele with a frequency of 0.371 was obtained in this study. The knowledge of distribution on allelic variants at the locus αS1 - casein in the population of Balkan goats will contribute to a better valorization and improving of this breed and the preservation of its genetic variability.

/pdf/gene-frequencies-of-caprine-alpha-s1-casein-polymorphism-in-4jd0o14y5t.pdf

Snezana Jovanovic

Papers

In vitro and in vivo anti-tumor effects of selected platinum(IV) and dinuclear platinum(II) complexes against lung cancer cells

Mechanistic insight on the chemistry of potential Pt antitumor agents as revealed by collaborative research performed in Kragujevac and Erlangen

Gene frequencies of Caprine alpha S1 casein polymorphism in Montenegrian Balkan goat breed