Synthesis and Biological Activity Evaluations of Novel Heterobimetallic Platinum(II)–Gold(I) Complexes as Bio-imaging Agents.

Introduction: Platinum-based drugs have become a mainstay of cancer therapy, approximately half of all patients undergoing chemotherapeutic treatment receive a platinum drug. Despite the pervasiveness of platinum drugs in cancer treatment regimens, a number of attendant disadvantages such as resistance to some cancer types and side effects exist. Gold complexes are also emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. Methods and Results: Here, some novel heterobimetallic platinum(II)–gold(I) complexes were synthesized and their cytotoxic activities against different human cancer cell lines such as A549 (human lung cancer), SKOV3 (human ovarian cancer) and MDA-MB-231 (human breast cancer) were evaluated. Electrophoresis mobility shift assay and molecular modeling investigations have been performed to determine the specific binding mode or the binding orientation of these compounds to DNA. Molecular docking studies of them on DNA were performed by means of AutoDock 4.2. Fluorescence emission properties of them were assessed using fluorescent microscopy imaging. In comparison to cis-platin, these compounds displayed significantly higher in vitro cytotoxicity on the studied cell lines. They enter SKOV3 cells rapidly, retaining their phosphorescence and localise simultaneously in cytoplasm, especially in perinuclear regions. So they are suitable candidates for time resolved emission imaging microscopy (TREM). Electrophoresis mobility shift assay showed a little shift and little interaction with plasmid DNA, though this shift is not as much as cis-platin. They may exert their cytotoxic effect through a different mechanism. Conclusions: According to the results, careful drug design would result in producing potential antitumor agents with high efficacy. These Pt(II)-Au(I) complexes can be used in biological labelling and cellular imaging studies, due to desirable absorption and emission of them in solution under ambient conditions. Hence, they had a potential value for drug development as anticancer agents

QSAR, Molecular Docking and protein ligand interaction fingerprint studies of N-phenyl dichloroacetamide derivatives as anticancer agents

Dichloroacetate (DCA) is a pyruvate mimetic compound that stimulates the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA works by turning on the apoptosis which is suppressed in tumor cells, hence let them to die on their own. Here, in this paper a series of DCA analogues were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), simple Free-Wilson analysis (FWA) and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were conducted to make relations between structural features and cytotoxic activities of a variety of DCA derivatives. The best multiple linear regression equation obtained from genetic algorithms partial least squares which predict 91% of variances. On the basis of the produced model, an in silico-screening study was also employed and new potent lead compounds based on new structural patterns were suggested. Docking studies of these compounds were also investigated and promising results were obtained. The docking results were also conducted to protein ligand interaction fingerprints (PLIF) studies using self-organizing map (SOM) in order to evaluate the predictive ability in suggesting new potent compounds and some compounds were introduced as a good candidates for synthesis.</p

Cyclometalated platinum(II) complexes of 2,2'-bipyridine N-oxide containing 1,1'-bis(diphenylphosphino)ferrocene ligand: Structural, computational and electrochemical studies

The preparation and characterization of new heteronuclear-platinum(II) complexes containing 1,1'-bis(diphenylphosphino)ferrocene (dppf) ligand are described. The reaction of the known starting complex [PtMe(κ2N,C-bipyO-H)(SMe2)], A, in which bipyO-H is a cyclometalated “rollover” 2,2'-bipyridine N-oxide, with the dppf ligand in a 2 : 1 ratio or an equimolar ratio led to the formation of corresponding binuclear complex [Pt2Me2(κ2N,C-bipyO-H)2(µ-dppf)], 1, or mononuclear complex [PtMe(κ1C-bipyO-H)(dppf)], 2, respectively. According to the reaction conditions, the dppf ligand in 1 and 2 behaves as either a bridging or chelateing ligand. All complexes were characterized by NMR spectroscopy. The solid-state structure of 2 was determined by single-crystal X-ray diffraction method and it was shown that the chelateing dppf ligand in this complex was arranged “synclinal-staggered” conformation. Also, the occurrence of intermolecular C–HCp…ObipyO-H interactions in the solid-state gave rise to an extended 1-D network. The electronic absorption spectra and the electrochemical behavior of these complexes are discussed. Density functional theory (DFT) was used for geometry optimization of the singlet states in solution and for electronic structure calculations. The analysis of the molecular orbital (MO) compositions in terms of occupied and unoccupied fragment orbitals in 2 was performed

Cyclometalated platinum(II) complexes of 2,2'-bipyridine N-oxide containing 1,1'-bis(diphenylphosphino)ferrocene ligand: Structural, computational and electrochemical studies

Two cycloplatinated rollover complexes containing dppf ligand were synthesized and characterized.</p

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin

Design, synthesis, molecular docking and cytotoxic activity evaluations of novel piperidine and piperazine derivatives of dichloroacetate as potential anticancer agents

1273-1278Dichloroacetate (DCA) as a small and active anticancer agent through inhibition of pyruvate dehydrogenase kinases (PDKs), prevents proliferation of tumor growth. In this research, a series of novel piperidine and piperazine derivatives of DCA have been designed and subjected to molecular docking studies. Based on the docking results, nine compounds with the lowest binding energy and better interaction with PDKs isoenzymes have been selected and synthesized. The cytotoxic activities of the synthesized compounds have been evaluated against HT-29 and MCF7 human cancer cell lines. These compounds show moderate potencies with much higher anticancer activity than DCA. The most active of the series, f1, showed IC50 value of 7.79 µM against HT-29 cell line

Cycloplatinated(II) Complexes Bearing 1,1′-Bis(diphenylphosphino)ferrocene Ligand: Biological Evaluation and Molecular Docking Studies

In this study, the cytotoxic activities of structurally related cycloplatinated(II) complexes containing chelating and bridging 1,1′-bis(diphenylphosphino)ferrocene (dppf) ligand derived from a wide range of C^N cyclometalating ligands (vpy = deprotonated 2-vinylpyridine, bzq = deprotonated benzo[h]quinoline, bpy = deprotonated 2,2′-bipyridine, bpyO = deprotonated 2,2′-bipyridine N-oxide, and ppy = deprotonated 2-phenylpyridine), were evaluated against human lung (A549), ovarian (SKOV3) and breast (MCF-7) cancer cell lines. The most cytotoxic compounds, 2a, 2c and 2d, effectively produced cell death by inducing apoptosis in the A549, SKOV3 and MCF-7 cancer cell lines. In addition, the molecular docking simulation was performed to determine the specific binding mode and the orientation of binding to DNA. According to the results of biological evaluation, the dppf-containing cycloplatinated(II) complexes exhibited strong interactions with DNA as well as high cytotoxicity and apoptosis-inducing activities to human cancer cell line. The present study suggests that precise rational design of new platinum-based complexes would result in the preparation of potential anticancer drugs, which can induce facile apoptosis

(Benzyl isocyanide)gold(I) pyrimidine‐2‐thiolate complex: Synthesis and biological activity

The reaction of [(Me2S)AuCl] with an equimolar amount of benzyl isocyanide (PhCH2NC) ligand led to the formation of complex [(PhCH2NC)AuCl] (1). The solid‐state structure of 1 was determined using the X‐ray diffraction method. Through a salt metathesis reaction, the chloride ligand in 1 was replaced by pyrimidine‐2‐thiolate (SpyN−) to afford the complex [(PhCH2NC)Au(η1‐S‐Spy)] (2), which was characterized spectroscopically. The cytotoxic activities of 1 and 2 were evaluated against three human cancer cell lines: ovarian carcinoma (SKOV3), lung carcinoma (A549) and breast carcinoma (MCF‐7). Complex 2 showed higher cytotoxicity than cisplatin against SKOV3 and MCF‐7 cancer cell lines. It showed a strong anti‐proliferative activity with IC50 of 7.80, 6.26 and 6.14 μM, compared with that measured for cisplatin which was 7.62, 12.36 and 11.47 μM, against A549, SKOV3 and MCF‐7 cell lines, respectively. The induction of cellular apoptosis by 2 was also studied on MCF‐7 cell line. Our results indicated that 2 could induce apoptosis in cancerous cells in a dose‐dependent manner