QSAR Studies of Copper Azamacrocycles and Thiosemicarbazones:  MM3 Parameter Development and Prediction of Biological Properties

Wolohan, Peter; Yoo, Jeongsoo; Welch, Michael J.; Reichert, David E.

doi:10.1021/jm0501376

Cited by 26 publications

(14 citation statements)

References 39 publications

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“…Thiosemicarbazones (TSCs) are a class of compounds of medicinal interest whose anticancer activity has been reported as early as 1960s [53,54] and their development is still in progress [55][56][57][58][59]. Some of them, such as Marboran TM or Triapine TM , are in the clinical practice [60].…”

Section: Thiosemicarbazone Complexesmentioning

confidence: 99%

“…Experiments in rats employing one of the most promising derivatives (55), showed a strong inhibition of cell proliferation against C6 glioma cells. Based on IC 50 values, (57) and (58) were shown to be almost 6 and 12 times more potent as antitumor agents than cisplatin, respectively. However, besides mitochondria, other potential cellular targets have been identified.…”

Section: Phenanthroline and Bipyridine Complexesmentioning

confidence: 99%

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Copper Complexes as Anticancer Agents

Marzano

Pellei²,

Tisato³

et al. 2009

ACAMC

727

395

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Metal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clinical use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. The variety of metal ion functions in biology has stimulated the development of new metallodrugs other than Pt drugs with the aim to obtain compounds acting via alternative mechanisms of action. Among non-Pt compounds, copper complexes are potentially attractive as anticancer agents. Actually, since many years a lot of researches have actively investigated copper compounds based on the assumption proposal that endogenous metals may be less toxic. It has been established that the properties of copper-coordinated compounds are largely determined by the nature of ligands and donor atoms bound to the metal ion. In this review, the most remarkable achievements in the design and development of copper(I, II) complexes as antitumor agents are discussed. Special emphasis has been focused on the identification of structure-activity relationships for the different classes of copper(I,II) complexes. This work was motivated by the observation that no comprehensive surveys of copper complexes as anticancer agents were available in the literature. Moreover, up to now, despite the enormous efforts in synthesizing different classes of copper complexes, very few data concerning the molecular basis of the mechanisms underlying their antitumor activity are available. This overview, collecting the most significant strategies adopted in the last ten years to design promising anticancer copper(I,II) compounds, would be a help to the researchers working in this field.

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Section: Thiosemicarbazone Complexesmentioning

confidence: 99%

Section: Phenanthroline and Bipyridine Complexesmentioning

confidence: 99%

Copper Complexes as Anticancer Agents

Marzano

Pellei²,

Tisato³

et al. 2009

ACAMC

727

395

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“…15,16 In this study we have combined these two topics by combining the development of a force field capable of modeling a wide variety of Re based estrogen ligands, and the use of molecular docking with full ligand flexibility to study their interactions with the estrogen receptor. Molecular docking studies have become an important method in structure based design, but have not been widely used with metal complexes.…”

Section: Introductionmentioning

confidence: 99%

CoMSIA and docking study of rhenium based estrogen receptor ligand analogs

Wolohan

Reichert

2007

Steroids

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OPLS all atom force field parameters were developed in order to model a diverse set of novel rhenium based estrogen receptor ligands whose relative binding affinities (RBA) to the estrogen receptor alpha isoform (ERα) with respect to 17β-Estradiol were available. The binding properties of these novel rhenium based organometallic complexes were studied with a combination of Comparative Molecular Similarity Indices Analysis (CoMSIA) and docking. A total of 29 estrogen receptor ligands consisting of 11 rhenium complexes and 18 organic ligands were docked inside the ligand-binding domain (LBD) of ERα utilizing the program Gold. The top ranked pose was used to construct CoMSIA models from a training set of 22 of the estrogen receptor ligands which were selected at random. In addition scoring functions from the docking runs and the polar volume (PV) were also studied to investigate their ability to predict RBA ERα. A partial least-squares analysis consisting of the CoMSIA steric, electrostatic and hydrophobic indices together with the polar volume proved sufficiently predictive having a correlation coefficient, r 2 , of 0.94 and a cross-validated correlation coefficient, q 2 , utilizing the leave one out method of 0.68. Analysis of the scoring functions from Gold showed particularly poor correlation to RBA ERα which did not improve when the rhenium complexes were extracted to leave the organic ligands. The combined CoMSIA and polar volume model ranked correctly the ligands in order of increasing RBA ERα, illustrating the utility of this method as a prescreening tool in the development of novel rhenium based estrogen receptor ligands.

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“…Indeed, they have found application in both the prediction of biological activity and more recently in the prediction of the absorption, distribution, metabolism, excretion and toxicological (ADME/tox) properties of organic drug-like compounds [15][16][17][18][19]. While QSAR methods have found many applications in the modeling of the properties of organic drug-like compounds they have found little application with radiometal complexes until our recent work, possibly due to the lack of the required metal-ligand parameters [20]. With the development of suitable metal-ligand force field parameters, the adoption of QSAR studies will no doubt aid the search for novel metal-based pharmaceuticals targeted towards biological receptors.…”

Section: Introductionmentioning

confidence: 99%