Oxidative halogenation of cisplatin and carboplatin: synthesis, spectroscopy, and crystal and molecular structures of Pt(<scp>iv</scp>) prodrugs

Johnstone, Timothy C.; Alexander, Sarah M.; Wilson, Justin J.; Lippard, Stephen J.

doi:10.1039/c4dt02627f

Cited by 53 publications

(60 citation statements)

References 72 publications

(116 reference statements)

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“…Carboplatin, cis ‐[Pt(cbdca)(NH 3 ) 2 ], was obtained from Tokyo Chemical Industry. The prodrug cis,trans ‐[Pt(cbdca)(NH 3 ) 2 Cl 2 ] was synthesized according to the published procedure , but starting from a larger scale (0.40 g carboplatin) and yielding 0.37 g of [Pt(cbdca)(NH 3 ) 2 Cl 2 ]·⅓DMF. Elemental analysis, theoretical: C, 18.01%; H, 3.07%; N, 7.01%.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Tian

Dong

Chi

et al. 2017

Int. J. Chem. Kinet.

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Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis-[Pt(NH 3 ) 2 Cl 4 ] and a carboplatin prodrug cis,trans-[Pt(cbdca)(NH 3 ) 2 Cl 2 ] by DL-homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second-order kinetics: −d[Pt(IV)]/dt = k [Hcy] tot [Pt(IV)], where [Hcy] tot stands for the total concentration of Hcy and k pertains to the observed second-order rate constants. The k versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of [Pt(IV)]: [Hcy] tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high-resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate-determining steps, resulting in a Cl + transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants An Accumet Basic AB15 Plus pH meter, equipped with an Accumet AccutupH R combination pH electrode (Fisher Scientific, Pittsburgh, PA), was used to measure the pH values of buffer solutions. Each time, the electrode was calibrated using the standard buffers

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Section: Methodsmentioning

confidence: 99%

“…We have investigated kinetically and mechanistically the reduction reactions of two interesting prodrugs, which are a cisplatin prodrug cis ‐[Pt(NH 3 ) 2 Cl 4 ] and a carboplatin prodrug cis,trans ‐[Pt(cbdca)(NH 3 ) 2 Cl 2 ] (cbdca = cyclobutane‐1,1‐dicarboxylate) by Hcy; their structures are given in Fig. .…”

Section: Introductionmentioning

confidence: 99%

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Tian

Dong

Chi

et al. 2017

Int. J. Chem. Kinet.

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“…The chelating dicarboxylate leaving group is hydrolyzed more slowly than the monodentate chlorido ligands in cisplatin, thus reducing off-target binding to biomolecules prior to DNA coordination. Platinum(IV) complexes based on carboplatin have been synthesized with various biologically inactive axial ligands and their pharmacokinetic properties and structure-activity relationship have been studied [16][17][18][19][20]. A Pt(IV) prodrug of carboplatin has also been modified with a polymeric nanodelivery carrier [21].…”

Section: Introductionmentioning

confidence: 99%

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Almotairy

Gandin

Morrison

et al. 2017

Journal of Inorganic Biochemistry

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Five new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by H andPt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH)(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH)(PBA)] (2), cis,trans-[Pt(CBDCA)(NH)(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH)(PBA)(suc)] (4) and cis,trans-[Pt(CBDCA)(NH))(PBA)(ac)] (5) (PBA=4-phenylbutyrate, CBDCA=1,1-cyclobutane dicarboxylate, bz=benzoate, suc=succinate and ac=acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells.

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“…However, these compounds cause tumor cell death following same mechanism as alkylating agents. Recently, Lippard and co-workers developed a series of Pt (IV) prodrugs of cisplatin and carboplatin bearing axial halides by oxidative halogenation [166, 167]. Similarly derivatives of oxaliplatin with axial valproato ligands were developed [168].…”

Section: Prodrug Approach: Analog / Chemical Conjugation For Cancementioning

confidence: 99%

Novel delivery approaches for cancer therapeutics

Mitra

Agrahari

Mandal

et al. 2015

Journal of Controlled Release

138

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Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering, multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer.

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Oxidative halogenation of cisplatin and carboplatin: synthesis, spectroscopy, and crystal and molecular structures of Pt(iv) prodrugs

Cited by 53 publications

References 72 publications

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Novel delivery approaches for cancer therapeutics

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