Computational assessment of the use of graphene-based nanosheets as PtII chemotherapeutics delivery systems.

Graphene is the newest form of elemental carbon and it is becoming rapidly a potential candidate in the framework of nano-bio research. Many reports confirm the successful use of graphene-based materials as carriers of anticancer drugs having relatively high loading capacities compared with other nanocarriers. Here, the outcomes of a systematic study of the adsorption behavior of FDA approved PtII drugs cisplatin, oxaliplatin, and carboplatin on surface models of pristine, holey, and nitrogen-doped holey graphene are reported. DFT investigations in water solvent have been carried out considering several initial orientations of the drugs with respect to the surfaces. Adsorption free energies, calculated including basis set superposition error (BSSE) corrections, result to be significantly negative for many of the drug@carrier adducts indicating that tested layers could be used as potential carriers for the delivery of anticancer PtII drugs. The reduced density gradient (RDG) analysis allows to show that many kinds of non-covalent interactions, including canonical H-bond, are responsible for the stabilization of the formed adducts.

Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity.

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells.

Will the Interactions of Some Platinum (II)-Based Drugs with B-Vitamins Reduce Their Therapeutic Effect in Cancer Patients? Comparison of Chemotherapeutic Agents such as Cisplatin, Carboplatin and Oxaliplatin-A Review.

Pt (II) derivatives show anti-cancer activity by interacting with nucleobases of DNA, thus causing some spontaneous and non-spontaneous reactions. As a result, mono- and diaqua products are formed which further undergo complexation with guanine or adenine. Consequently, many processes are triggered, which lead to the death of the cancer cell. The theoretical and experimental studies confirm that such types of interactions can also occur with other chemical compounds. The vitamins from B group have a similar structure to the nucleobases of DNA and have aromatic rings with single-pair orbitals. Theoretical and experimental studies were performed to describe the interactions of B vitamins with Pt (II) derivatives such as cisplatin, oxaliplatin and carboplatin. The obtained results were compared with the values for guanine. Two levels of simulations were implemented at the theoretical level, namely, B3LYP/6-31G(d,p) with LANL2DZ bases set for platinum atoms and MN15/def2-TZVP. The polarizable continuum model (IEF-PCM preparation) and water as a solvent were used. UV-Vis spectroscopy was used to describe the drug-nucleobase and drug-B vitamin interactions. Values of the free energy (ΔGr) show spontaneous reactions with mono- and diaqua derivatives of cisplatin and oxaliplatin; however, interactions with diaqua derivatives are more preferable. The strength of these interactions was also compared. Carboplatin products have the weakest interaction with the studied structures. The presence of non-covalent interactions was demonstrated in the tested complexes. A good agreement between theory and experiment was also demonstrated.

Surrounded by ligands: the reactivity of cisplatin in cell culture medium.

The reactivity of platinum-containing drugs such as cisplatin, carboplatin, and oxaliplatin is essential for its mechanism of action as an anticancer agent. This inherent reactivity means that molecules in tools used to study these metal-based drugs such as solvents (DMSO), cell culture media, and other buffer additives can ligate to and inactivate or activate them. This Commentary considers these cautionary tales in the context of a new report that cisplatin can also react with penicillin, reiterates best practice in creating Pt drug stock solutions, and highlights the significant work that remains to fully characterize the fate of cisplatin in cell culture media.

Evaluation of amentoflavone metabolites on PARP-1 inhibition and the potentiation on anti-proliferative effects of carboplatin in A549 cells.

The present study aims to determine the major metabolites of amentoflavone (AMF) and further evaluate their inhibitory effects on PARP-1. First, different fractions (Frs. 1-9), which were collected according to retention time of AMF metabolites based on UHPLC-QTOF-MS/MS qualitative analysis, were evaluated on their inhibitory effects against PARP-1. Then, two mono-sulfate metabolites in the fractions with potent PARP-1 inhibitory effect were targetedly semi-synthesized. Moreover, three mono-sulfate conjugates (compound 8, 9 and 10), including one disulfate conjugate (compound 10), were isolated and their structures were fully elucidated by UHPLC-QTOF-MS/MS and NMR. Finally, the binding mode of compound 8 (amentoflavone-4‴-O-sulfate) toward PARP-1 and its potentiation on carboplatin (CBP) in A549 cells were investigated. This study was the first report on bioactivity evaluation of AMF metabolites in rat bile on PARP-1 and the potentiation of compound 8 on carboplatin (CBP) in A549 cells in vitro. This paper also provided scientific basis for the AMF metabolites on PARP-1 inhibition and chemosensitization.

Anti-tumor effects and cell motility inhibition of the DN604-gemcitabine combined treatment in human bladder cancer models.

Bladder cancer is one of the major tumors for men in the world, in which therapy the combination of cisplatin and gemcitabine is still fist-line applied to treat with advanced or metastatic bladder cancer. In our early study, we developed a potential Pt(II) agent, DN604, which has anti-tumor effect as potent as cisplatin toward bladder cancers. Herein, we aim at investigating the combinatory application of DN604 with gemcitabine for bladder cancer treatment. In vitro studies proved that the combined treatment of DN604 and gemcitabine could limit cell proliferation by elevating the incidence of DNA damage induced apoptosis. Notably, further researches showed that the DN604-gemcitabine treatment suppressed cell autophagy to inhibit cell motility upon the ROS dependent p38 MAPK signaling pathway, explicating its better anti-tumor activity than single drug treatment or the cisplatin-gemcitabine treatment. In vivo tests confirmed that the DN604-gemcitabine treatment has superior anti-tumor activity with low toxicity to cisplatin or its combination with gemcitabine treatments. DN604 plus gemcitabine, is of great significance for the treatment with human bladder cancer. Our study has provided a potential combination treatment option.

The Affinity of Carboplatin to B-Vitamins and Nucleobases.

Platinum compounds have found wide application in the treatment of various types of cancer and carboplatin is one of the main platinum-based drugs used as antitumor agents. The anticancer activity of carboplatin arises from interacting with DNA and inducing programmed cell death. However, such interactions may occur with other chemical compounds, such as vitamins containing aromatic rings with lone-pair orbitals, which reduces the anti-cancer effect of carboplatin. The most important aspect of the conducted research was related to the evaluation of carboplatin affinity to vitamins from the B group and the potential impact of such interactions on the reduction of therapeutic capabilities of carboplatin in anticancer therapy. Realized computations, including estimation of Gibbs Free Energies, allowed for the identification of the most reactive molecule, namely vitamin B6 (pyridoxal phosphate). In this case, the computational estimations indicating carboplatin reactivity were confirmed by spectrophotometric measurements.

Synthesis and in vitro antitumour activity of carboplatin analogues containing functional handles compatible for conjugation to drug delivery systems.

We describe herein the synthesis of a series of carboplatin derivatives with different functional groups at position 3 of the cyclobutane ring. This pharmacomodulation approach aims at facilitating the vectorisation of these analogues, via their subsequent conjugation to a drug delivery system. Five different derivatives bearing a hydroxy, keto, iodo, azido or amino function at position 3 were synthesised. One of these compounds was coupled to a bifunctional maleimide-containing linker. All compounds were tested in vitro for their cytotoxicity on four different cell lines including two platinum-resistant colorectal cancer cell line (SK-OV-3, HCT116, D3E2, D5B7) using an MTS assay. Overall, the tested compounds were up to six times more potent than carboplatin, especially on D5B7 human colorectal cancer cells. We demonstrated that these modifications led to potent analogues which are compatible with conjugation to a drug delivery system.

BODI-Pt, a Green-Light-Activatable and Carboplatin-Based Platinum(IV) Anticancer Prodrug with Enhanced Activation and Cytotoxicity.

Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their clinical use. The conversion of platinum(II) drugs into more inert platinum(IV) derivatives is a promising strategy to solve this problem. Some platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum(IV) prodrugs.

Combination of DN604 with gemcitabine led to cell apoptosis and cell motility inhibition via p38 MAPK signaling pathway in NSCLC.

Non-small-cell lung cancer (NSCLC) is the most common cancer in the world, which is still treated with Pt(II) agents as first-line drugs. As a traditional anticancer agent, gemcitabine is usually used in the combination treatment of various solid tumors with other drugs. Here, we investigate the combinatory application of gemcitabine with a Pt(II) agent (DN604, reported previously in our former research) in the treatment of NSCLC. In vitro biological assays suggested that DN604-gemcitabine treatment can effectively induce cell apoptosis and suppress cell motility, showing better anti-tumor effect than the single drug treatment or the combined treatment of cisplatin and gemcitabine. More importantly, investigation on the mechanism of the combined treatment proved that such combined treatment can suppress cell autophagy to inhibit cell motility via the activation of p38 MAPK signaling pathway. In vivo studies indicated that combination of DN604 with gemcitabine significantly inhibited the growth of tumor with nearly no influence on the normal organs and weight of mice. Our study widened the application scope of Pt(II) agents combined with gemcitabine for NSCLC treatment.

Repeatability of in vitro carboplatin elution from carboplatin-impregnated calcium sulfate hemihydrate beads made in a clinic setting.

OBJECTIVE: To evaluate the intra-lot and inter-lot consistency and total carboplatin elution over 25 days from carboplatin-impregnated calcium sulfate hemihydrate (C-I CSH) beads manufactured in a clinic setting. STUDY DESIGN: In vitro elution study. METHODS: Two volumes of carboplatin were mixed with CSH to yield 4 mg and 8 mg C-I CSH doses. Two lots of beads were made for each concentration and split into five doses (n = 10 per concentration). Beads hardened in molds and were placed in a covered six-well plate, submerged in phosphate-buffered saline, and incubated with samples collected at 12 time points (0, 6, 12, and 24 hours and 2, 3, 5, 7, 10, 14, 18, and 25 days). The amount of carboplatin in each sample was evaluated by high-performance liquid chromatography/mass spectrometry. Correction for carboplatin degradation and dilution was applied, and eluted carboplatin was calculated. Intra-lot and inter-lot coefficient of variation (CV) was calculated for each concentration. RESULTS: The intra-lot CV ranged between 7.9% and 23.1%, and the inter-lot CV ranged from 3.5% to 10.3%, with improvement noted in each successive lot of beads. Mean peak eluted carboplatin was 2.45 ± 0.43 mg (61%) and 3.68 ± 0.41 mg (45.9%) for the 4-mg and 8-mg C-I CSH beads, respectively, with both occurring at the 12-hour timepoint. CONCLUSION: Progressive improvement in variability with successive lots of beads indicated a learning curve with bead manufacturing with a low variation both within and between lots of C-I CSH beads. CLINICAL SIGNIFICANCE: On-site mixing of carboplatin with commercial CSH bead powder leads to a low variation of carboplatin per bead dose.

In Vitro MCF-7 Cells Apoptosis Analysis of Carboplatin Loaded Silk Fibroin Particles.

Breast cancer ranks as the fifth leading cause of death worldwide. Chemotherapy is commonly used directly or as neo-adjuvant therapy for the management of breast cancer with its attendant adverse effects, underscoring the need to develop biocompatible bioactive compounds for pharmacological applications. The aim of this study is to encapsulate carboplatin (CP) with silk fibroin protein (SF) by using an ionic gelation method as a drug carrier system and assess the apoptotic effect on MCF-7 breast cancer cells during in vitro studies. The characterization of silk fibroin encapsulated carboplatin (SFCP) microparticles was analyzed by FTIR spectrophotometer, SEM, Mastersizer, and biodegradation methods. The encapsulation efficiency and release profile of SFCP microparticles were analyzed by an indirect UV-Vis spectrophotometric method. An apoptotic screening of MCF-7 cells was carried out with 10-200 µg/mL CP loaded SFCP, which were cultured for 24, 48, and 72 h. Data were analyzed using the Student's t test and analysis of variance. FTIR and drug release studies confirmed an interaction of silk fibroin with the carboplatin moiety. SFCP showed successful encapsulation of the carboplatin moiety. Apoptotic screening showed a dose dependent increase in absorbance, indicating significant cell death (p < 0.05). Thus, the direct apoptotic effect of SFCP microparticles on MCF-7 was confirmed.

The leading established metal-based drugs: a revisitation of their relevant physico-chemical data.

The study of metal-based drugs represents an important branch of modern bioinorganic chemistry. The growing importance of this field is linked to the large success in medicine of a few metal based drugs, either in clinical use or still experimental. Moreover, these metal-based drugs are frequently used as reference compounds to assess comparatively the behavior of newly synthesized metallodrugs. For the convenience of researchers working in this area we report here a compilation of the relevant analytical and spectroscopic data of ten representative metallodrugs based on Platinum, Ruthenium, Gold and Mercury. The selected compounds, namely Cisplatin, Oxaliplatin, Carboplatin, Auranofin, Sodium Aurothiomalate, NAMI-A, KP1019, Thimerosal, Merbromin and Phenylmercury Acetate, were chosen owing to their importance in the field. We believe that this compilation may turn very helpful to researchers as these data are difficult to find and generally scattered over a large number of (old) publications.

DN604: A platinum(II) drug candidate with classic SAR can induce apoptosis via suppressing CK2-mediated p-cdc25C subcellular localization in cancer cells.

DN604, a carboplatin analogue with a functional dicarboxylato ligand, was deeply investigated to explore its ability to induce apoptosis as well as its antitumor mechanism of action. Both in vitro and in vivo assays indicated that DN604 could effectively inhibit cell viability of SGC-7901 gastric cancer cells and exhibited stronger antitumor activity than carboplatin and comparable activity to cisplatin. Significantly in contrast to cisplatin, DN604 resulted in negligible toxic effects in vivo with the same tumor growth inhibition effect as cisplatin. The mechanism study indicated that DN604 inhibited CK2-phosphorylated cdc25C activation to decrease p-cdc25C subcellular localization, leading to the inactivation of cdc2/Cyclin B and G2/M cell cycle arrest and apoptosis in SGC-7901 cancer cells. Our research revealed for the first time that the dicarboxylato ligand containing a suitable functional moiety as the leaving group in the platinum(II) complex can effectively induce cell cycle arrest and apoptosis via inhibiting key checkpoint proteins.

Stability of carboplatin infusion solutions used in desensitization protocol.

Carboplatin hypersensitivity reactions are one of the major clinical challenges in treating patients with relapse/recurrent ovarian malignancies. Desensitization protocols allow the continuation of treatment in patients who have presented hypersensitivity reactions by gradually re-introducing small amounts of the drug up to full therapeutic doses. Carboplatin desensitization protocol is based on three solutions that are usually prepared in the chemotherapy centralized units of hospital pharmacies. First and second solutions are diluted under the established concentration limit to guarantee the stability of the preparation. We developed a specific high-performance liquid chromatography assay to determine the stability of carboplatin infusion solutions that have been diluted to 0.2 mg/mL and 0.02 mg/mL in 250 mL of 5% dextrose in polypropylene infusion bags which were stored 24 h protected from light at room temperature. Samples were withdrawn at t = 0 h, 3 h, 6 h, and 24 h. The analytical column was a Zorbax eclipse XDB-C18 (150 mm × 4.6 mm; 5 µm particle size). The mobile phase had a flow rate of 1 mL/min under isocratic conditions of water-methanol (98:2, v/v). For 0.2 mg/mL solution, the high-performance liquid chromatography assay revealed no significant losses in carboplatin concentration. However, in 0.02 mg/mL solution remaining carboplatin was > 105% the initial dose after 3 h of storage at room temperature. The ultraviolet-visible spectra analysis showed that carboplatin remained intact during the study in 0.2 mg/mL solution, but some changes were detected in 0.02 mg/mL solution. Thus, 0.2 mg/mL carboplatin solution is stable for 24 h at room temperature in 5% dextrose polypropylene infusion bags but stability could not be proved for 0.02 mg/mL solution.

Investigations of the Kinetics and Mechanism of Reduction of a Carboplatin Pt(IV) Prodrug by the Major Small-Molecule Reductants in Human Plasma.

The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys-Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k' followed the order Asc << Cys-Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (-SCH2CH(NH3+)COO-) and species IV of GSH (-OOCCH(NH3+)CH2CH2CONHCH(CH2S-)- CONHCH2COO-) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.

Clustered DNA Damages induced by 0.5 to 30 eV Electrons.

Low-energy electrons (LEEs) of energies ≤30 eV are generated in large quantities by ionizing radiation. These electrons can damage DNA; particularly, they can induce the more detrimental clustered lesions in cells. This type of lesions, which are responsible for a large portion of the genotoxic stress generated by ionizing radiation, is described in the Introduction. The reactions initiated by the collisions of 0.5-30 eV electrons with oligonucleotides, duplex DNA, and DNA bound to chemotherapeutic platinum drugs are explained and reviewed in the subsequent sections. The experimental methods of LEE irradiation and DNA damage analysis are described with an emphasis on the detection of cluster lesions, which are considerably enhanced in DNA-Pt-drug complexes. Based on the energy dependence of damage yields and cross-sections, a mechanism responsible for the clustered lesions can be attributed to the capture of a single electron by the electron affinity of an excited state of a base, leading to the formation of transient anions at 6 and 10 eV. The initial capture is followed by electronic excitation of the base and dissociative attachment-at other DNA sites-of the electron reemitted from the temporary base anion. The mechanism is expected to be universal in the cellular environment and plays an important role in the formation of clustered lesions.

Platinum(II) complexes of imidazophenanthroline-based polypyridine ligands as potential anticancer agents: synthesis, characterization, in vitro cytotoxicity studies and a comparative ab initio, and DFT studies with cisplatin, carboplatin, and oxaliplatin.

The synthesis of the platinum(II) complexes, [Pt(AIP)(bpy)](PF6)2 (1) and [Pt(PIP)(phen)](PF6)2 (2), of anthracene- and pyrene-conjugated imidazophenanthroline ligands and their in vitro cytotoxicity toward the fibroblast cells and the HeLa cell lines are reported. MTT assay demonstrates their cytotoxicity against the HeLa cell lines with the IC50 values of 1.35 and 1.56 µM, respectively, and the cytotoxicity profiles indicate that the HeLa cell lines show more activity than the fibroblast cells. Trypan blue assay highlights significant damage on the HeLa cell lines with a pronounced reduction on their clonogenicity. AO/EB staining shows marked morphologic signs of apoptosis in a dose-dependent manner and the LDH and DNA laddering assays also lend support to the cytotoxicity of the complexes. The molecular docking study reveals that the complexes interact with DNA through hydrogen bonding. The TD-DFT energy-optimized structures of the complexes show that the platinum(II) center has a slightly distorted square-planar geometry. The TD-DFT modelled LUMOs receive major contributions from the platinum d-orbitals, while the HOMOs are delocalized largely on the anthracenyl- and pyrenyl ligands, resulting in the LMCT transition at 352 nm. The structural, bonding, electronic, and optical properties of the complexes 1 and 2 reported in the present work and that of [Pt(AIP)(phen)](PF6)2 (3) and [Pt(PIP)(bpy)](PF6)2 (4), reported by us recently, and the approved drugs cisplatin, carboplatin, and oxaliplatin are described in the light of the optimized geometries, ΔEHOMO-LUMO, polarizability (α), hyperpolarizability (ß), Mulliken negativities, and dipole moments computed from the ab initio and DFT computational studies. The synthesis of Pt(II) complexes of anthracene- and pyrene-appended imidazophenanthroline ligands and their in vitro cytotoxicity against fibroblast cells and HeLa cell lines are reported. The DFT computational study of the complexes and cisplatin, carboplatin, and oxaliplatin are described in search of the ligand design features for the development of new Pt-drugs.

Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel.

Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.

Raman and Infrared Studies of Platinum-Based Drugs: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, and Heptaplatin.

This study reports the optimized structures and lowest-energy conformations/stereochemistry of five currently used platinum-based drugs: cisplatin, carboplatin, nedaplatin, oxaliplatin, and heptaplatin. Normal Raman and IR spectra of each drug are experimentally obtained and have been compared to various levels of density functional theory (DFT). Although some combination of structure, reactivity, or spectroscopy for these drugs has been studied by various groups, there are no known experimental normal Raman and IR spectra for nedaplatin, oxaliplatin, and heptaplatin in the literature. The detailed structural and vibration findings of these drugs are very important to understanding platinum behavior and drug dynamics. The following work explores the vibrational frequencies of these drugs particularly by focusing on the low-energy modes between 200 and 600 cm-1, where anharmonicity effects will have less influence on the accuracy of computed frequencies. Ideally, the Pt-N stretching modes provide vibrational diagnostics for each drug. Interestingly, a vibrational energy decomposition analysis (VEDA) suggests that oxaliplatin and heptaplatin Pt-N stretching modes are not Raman or IR active. Instead, C-C and Pt-O stretching frequencies in the various bidentate dioxo ligands might be more useful in characterizing new cisplatin derivatives. Analysis of anharmonicity effects was compared against (and in tandem with) dimer computations of four of the five drugs. Harmonic vibrational computations of the dimeric cisplatin derivatives provided greater qualitative improvement than that of the monomeric derivatives. Satisfying agreement with experimental Raman spectra was obtained, even without resorting to linear scale factors for the harmonic dimer frequencies.