Combining the platinum(<scp>ii</scp>) drug candidate kiteplatin with 1,10-phenanthroline analogues

Pages, Benjamin J.; Sakoff, Jennette A.; Gilbert, Jayne; Zhang, Yingjie; Kelly, Sharon M.; Hoeschele, James D.; Aldrich‐Wright, Janice R.

doi:10.1039/c7dt04108j

Cited by 8 publications

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“…However, this eventuality is unlikely since it has been found 29−31 that the platinum(II)−oxalate complex with RR-DACH (1) was more active than the corresponding complexes with SS-DACH, 29−31 whereas platinum(II)−complex 5 with RR-DACH was less active than the corresponding complexes with SS-DACH. 32 An intriguing potency of the compounds based on 5 was observed for breast cancer cells MDA-MB-231 and colon carcinoma cells HCT-116 [for instance, the IC 50 values found for the investigated Pt(IV) derivatives of 5 were as low as 0.06−0.07 μM (Table 1)], that is, by approximately two orders of magnitude lower than the IC 50 values found for clinically used anticancer platinum drugs. A common feature of these cancer cells is that both carry RAS mutation that can cause the tumor to become resistant to drugs usually used to treat these types of cancer cells.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

“…Thus, it is possible to speculate that the considerable differences in antiproliferative activities observed for the compounds based on 1 and 5 (Table ) might also be a consequence of different enantiomericity of their amine ligands. However, this eventuality is unlikely since it has been found − that the platinum(II)–oxalate complex with RR -DACH ( 1 ) was more active than the corresponding complexes with SS -DACH, − whereas platinum(II)–complex 5 with RR -DACH was less active than the corresponding complexes with SS -DACH …”

Section: Resultsmentioning

confidence: 99%

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A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton

et al. 2019

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The substitution inert platinum agent [Pt(1S,2Sdiaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] 2+ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.

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Section: ■ Results and Discussionmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton

et al. 2019

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“…Os espectros de RMN de 1 H dos derivados de 5-alquil-1,3,4-oxadiazol-2-tiona apresentaram sinais característicos de alcanos na região entre δ 0,8-2,7 ppm, bem como a presença de um singleto largo referente ao hidrogênio NH do anel 1,3,4-oxadiazol em torno de Enquanto que no complexo 7 foram observados sinais localizados em δ 7,80; 7,98; 8,74 e 9,68 ppm que são atribuídos aos hidrogênios da fenantrolina (KOTZÉ et al, 2009;PAGES et al, 2018…”

Section: Rmn De 1 Hunclassified

Obtenção de complexos de Pt(II) e Pd(II) derivados de 1,3,4-oxadiazol-2-(3H)-tiona e 5-amino-1,3,4-tiadiazol-2-tiol: potencial antitumoral de dois complexos de Pt(II) contendo 1,10-fenantrolina

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Metal-based drugs have been developed in order to minimize side effects and/or to overcome intrinsic or acquired resistance to antitumor drugs available in medical clinics. In this sense, we are also looking for new pharmacological agents capable of curing or at least prolonging the survival of patients with tumors classified as incurable until then. Considering the need for rational production of new antitumor agents, this work describes the synthesis and structural characterization of new complexes of Pt (II) and Pd (II) of the type [M(L1)2(L2)2] (L1 = derived from 5-alkyl-1,3,4-oxadiazole-2-thione (5-alkyl-odztH) and L2 = triphenylphosphine) and of the type [M(L1)2L2] (L1 = derived from 5-alkyl-odztH or 5-amino-1,3,4-thiadiazole-2-thiol (5amino-tdztH) and L2 = 1,10-phenanthroline). The platinum and palladium complexes were characterized by elemental analysis, conductivity measurements, high-resolution electrospray ionization mass spectrometry (HRESIMS), infrared spectroscopy (FT-IR) and multinuclear NMR spectroscopy. Three complexes of the type [Pt(L1)2(PPh3)2] and one complex of the type [Pt(L1)2fen] had their crystalline structures determined by single-crystal X-ray diffraction. In all the complexes, the metal ion was coordinated with the two L1 ligands via a sulfur atom, in which two triphenylphosphine molecules or one phenanthroline molecule completes its coordination sphere. The molar conductivity values of 1.0 × 10 −3 mol L −1 solutions confirm that the complexes are non-electrolytes. The cytotoxic activity of the [Pt(heptyl-odzt)2fen] and [Pt(nonyl-odzt)2fen] complexes was evaluated in two tumor-cell lines (MCF-7 and MDA-MB-231), with the complex [Pt(5-nonil-odztH) 2 fen] being more active in both, since their IC50 values were lower. DNA interaction studies for both complexes reveled Kb values on the order of 10 4 M −1 , with no variation observed in positive or negative bands of circular dichroism (CD) spectra. In turn, in the fluorescence spectra of the Hoechst-DNA system, an observed reduction in fluorescence intensity indicated that these complexes interact with DNA through the minor groove.

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One‐pot Synthesis of 4‐Aminocyclohexanol Isomers by Combining a Keto Reductase and an Amine Transaminase

et al. 2019

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The efficient multifunctionalization by one-pot or cascade catalytic systems has developed as an important research field, but is often challenging due to incompatibilities or crossreactivities of the catalysts leading to side product formation. Herein we report the stereoselective preparation of cis-and trans-4-aminocyclohexanol from the potentially bio-based precursor 1,4-cyclohexanedione. We identified regio-and stereoselective enzymes catalyzing reduction and transamination of the diketone, which can be performed in a one-pot sequential or cascade mode. For this, we identified regioselective keto reductases for the selective mono reduction of the diketone to give 4-hydroxycyclohexanone. The system is modular and by choosing stereocomplementary amine transaminases, both cisand trans-4-aminocyclohexanol were synthesized with good to excellent diastereomeric ratios. Furthermore, we identified an amine transaminase that produces cis-1,4-cyclohexanediamine with diastereomeric ratios > 98 : 2. These examples highlight that the high selectivity of enzymes enable short and stereoselective cascade multifunctionalizations to generate high-value building blocks from renewable starting materials.

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Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

Cited by 8 publications

References 36 publications

A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton

A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton

Obtenção de complexos de Pt(II) e Pd(II) derivados de 1,3,4-oxadiazol-2-(3H)-tiona e 5-amino-1,3,4-tiadiazol-2-tiol: potencial antitumoral de dois complexos de Pt(II) contendo 1,10-fenantrolina

One‐pot Synthesis of 4‐Aminocyclohexanol Isomers by Combining a Keto Reductase and an Amine Transaminase

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