Correct Modeling of Cisplatin: a Paradigmatic Case

Tasinato, Nicola; Puzzarini, Cristina; Barone, Vincenzo

doi:10.1002/ange.201707683

Cited by 2 publications

(2 citation statements)

References 24 publications

(52 reference statements)

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“…This poses the challenge of a correct model to interpret the spectroscopic results. An illustrative example is provided by cisplatin, 48 for which the vibrational spectroscopic features can be correctly interpreted only if the essential intermolecular interactions are accounted for.…”

Section: Perspectivesmentioning

confidence: 99%

Diving for Accurate Structures in the Ocean of Molecular Systems with the Help of Spectroscopy and Quantum Chemistry

Puzzarini

Barone

2018

Acc. Chem. Res.

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The prediction and interpretation of structural properties are the starting points for a deep understanding of thermochemistry, kinetics, and spectroscopic signatures of molecular systems. To give an example, detailed knowledge of the conformational behavior of the main building blocks of biomolecules in the gas phase (i.e., without the perturbing effect of the environment) is a mandatory prerequisite toward the understanding of the role played by different interactions in determining the biological activity in terms of structure-activity relationships. The first step to take is an unambiguous definition of molecular structure. We address the so-called Born-Oppenheimer equilibrium structure, which is defined in a rigorous manner and isotopically independent, and the target accuracy. For the latter, we aim at so-called "spectroscopic" accuracy, which implies uncertainties of a few milliangstroms for bond lengths and smaller than a tenth of degree for angles. If on one side the continuous enhancements of the experimental techniques give access to new and unprecedented spectroscopic determinations, on the other side they require increasing efforts for an unbiased interpretation and analysis. Among the pieces of information, accurate molecular structures play a particularly important role. Indeed, there is a strong relationship between the experimental outcome and the electronic structure of the system. Spectroscopic techniques, in particular those exploited in the gas phase, are therefore accurate and reliable sources for structural information. However, it is seldom straightforward to derive molecular structures directly from the experimental information. Indeed, even in the favorable case of investigations in the gas phase, vibrational effects are always present, and disentangling their contributions requires collection of information for all vibrational modes, a nearly impossible task. To overcome these limitations, joint theory-spectroscopy strategies can be identified, which are referred to as "top-down" and "bottom-up". The first approach, denoted as the semiexperimental approach, relies on extracting from experimental outcomes the equilibrium structure by using quantum-chemical computations to recover vibrational effects. The bottom-up approach consists in verifying the computed equilibrium geometry by means of a comparison between calculated and experimental spectroscopic parameters that probe structural characteristics. In this contribution, we try to review the most important challenges in accurate molecular structure determinations, with particular emphasis on the "solution" provided by a joint theoretical-experimental approach and on the current state of the art. Starting from the illustration of different strategies, we proceed by addressing the increasing complexity in the derivation of equilibrium geometries: we start from the construction of a database of accurate structures, we then face the problem of extending the dimension of the systems amenable to accurate structural determinations, and finally...

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Section: Perspectivesmentioning

confidence: 99%

Diving for Accurate Structures in the Ocean of Molecular Systems with the Help of Spectroscopy and Quantum Chemistry

Puzzarini

Barone

2018

Acc. Chem. Res.

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“… 84 Further studies were conducted to describe the physicochemical properties of cisplatin through a model capable of quantitatively describing and interpreting the structural and vibrational properties. 85 …”

Section: Molecular Mechanisms Of Actionmentioning

confidence: 99%

Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy

Tchounwou

Dasari

Noubissi

et al. 2021

JEP

224

151

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Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head and neck, lung, ovarian, testicular cancers, and sarcoma. Cisplatin is commonly administered intravenously as a first-line chemotherapy for patients suffering from various malignancies. Upon absorption into the cancer cell, cisplatin interacts with cellular macromolecules and exerts its cytotoxic effects through a series of biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) and forming intra-strand DNA adducts leading to the inhibition of DNA synthesis and cell growth. Its primary molecular mechanism of action has been associated with the induction of both intrinsic and extrinsic pathways of apoptosis resulting from the production of reactive oxygen species through lipid peroxidation, activation of various signal transduction pathways, induction of p53 signaling and cell cycle arrest, upregulation of pro-apoptotic genes/proteins, and down-regulation of proto-oncogenes and anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies have reported substantial side effects associated with cisplatin monotherapy, while others have shown substantial drug resistance in some cancer patients. Hence, new formulations and several combinational therapies with other drugs have been tested for the purpose of improving the clinical utility of cisplatin. Therefore, this review provides a comprehensive understanding of its molecular mechanisms of action in cancer therapy and discusses the therapeutic approaches to overcome cisplatin resistance and side effects.

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Correct Modeling of Cisplatin: a Paradigmatic Case

Cited by 2 publications

References 24 publications

Diving for Accurate Structures in the Ocean of Molecular Systems with the Help of Spectroscopy and Quantum Chemistry

Diving for Accurate Structures in the Ocean of Molecular Systems with the Help of Spectroscopy and Quantum Chemistry

Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy

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