61825-94-3Relevant articles and documents
A Dual Killing Strategy: Photocatalytic Generation of Singlet Oxygen with Concomitant PtIV Prodrug Activation
Norman, Daniel J.,Gambardella, Alessia,Mount, Andrew R.,Murray, Alan F.,Bradley, Mark
, p. 14189 - 14192 (2019)
A ruthenium-based mitochondrial-targeting photosensitiser that undergoes efficient cell uptake, enables the rapid catalytic conversion of PtIV prodrugs into their active PtII counterparts, and drives the generation of singlet oxygen was designed. This dual mode of action drives two orthogonal cancer-cell killing mechanisms with temporal and spatial control. The designed photosensitiser was shown to elicit cell death of a panel of cancer cell lines including those showing oxaliplatin-resistance.
Comparison of N-acetylmethionine reactivity between oxaliplatin and an oxaliplatin derivative with chiral (S,S) amine nitrogen atoms
Williams, Kevin M.,Poynter, Amy D.,Hendrie, Jonathan D.,Jackson, Daniel C.,Martin, Virginia K.
, p. 64 - 69 (2013)
We have synthesized an oxaliplatin derivative using N,N′-dimethyl-1, 2-diaminocyclohexane (Me2dach) as the diamine ligand. The complex (S,R,R,S)-Pt(Me2dach)(oxalate), where S,R,R,S represents the chiralities at N,C,C,N, respectively, was prepared and characterized by 1H NMR spectroscopy, COSY, NOESY, and HMQC. Oxaliplatin reacts with N-acetylmethionine (N-AcMet) to form [Pt(dach)(N-AcMet-S)2] and [Pt(dach)(N-AcMet-S,N)], with the former favored at higher molar ratios of N-AcMet. In contrast, Pt(Me2dach)(oxalate) reacts to form [Pt(Me 2dach)(N-AcMet-S,O)]+ even in the presence of excess N-AcMet. Molecular mechanics calculations are consistent with significant steric clashes in models of [Pt(Me2dach)(N-AcMet-S)2]. When N-AcMet was reacted with an excess of each platinum complex, the rate of N-AcMet decrease was very similar for both complexes. Thus, the methyl groups at the nitrogen atoms had little to no effect on the addition of the sulfur atom of a single N-acetylmethionine, but they prevented chelation of the amide nitrogen or coordination of a second N-acetylmethionine residue.
Phorbiplatin, a Highly Potent Pt(IV) Antitumor Prodrug That Can Be Controllably Activated by Red Light
Wang, Zhigang,Wang, Na,Cheng, Shun-Cheung,Xu, Kai,Deng, Zhiqin,Chen, Shu,Xu, Zoufeng,Xie, Kai,Tse, Man-Kit,Shi, Peng,Hirao, Hajime,Ko, Chi-Chiu,Zhu, Guangyu
, p. 3151 - 3165 (2019)
Selective activation of prodrugs within a tumor is particularly attractive because of their low damage to normal tissue. Here, we report the design, photoactivation mechanism, and antitumor activity of a red-light-activatable Pt(IV) prodrug based on oxaliplatin, a first-line clinical antineoplastic. This small-molecule prodrug, designated as phorbiplatin, has controllable activation property: it is shown to be inert in the dark but under short-period irradiation with low intensity of red light (7 mW/cm2), without the need of any external catalyst, phorbiplatin is rapidly reduced to oxaliplatin. The prodrug displays photocytotoxicity that is up to 1,786 times greater than that of oxaliplatin in human carcinoma cells, and it is also significantly active in vivo. The controllable activation property and superior antitumor activity of phorbiplatin may suggest a novel strategy for the design of visible light-activatable platinum prodrugs to reduce the adverse effects and conquer drug resistance of traditional platinum chemotherapy. Currently, most of the small-molecule anticancer drugs used in clinics do not have controllable activation properties, leading to undesired side effects. Anticancer drugs with “on-site” activation properties are highly demanded. Here, we report the development of a small-molecule anticancer prodrug that can be controllably activated by a red light. The prodrug is stable in the dark even in a reducing environment and shows minimum dark toxicity to the cells. Under irradiation with low intensity of red light, the prodrug utilizes a unique photoactivation mechanism to be quickly and efficiently activated, releasing oxaliplatin, a widely used antineoplastic agent. The activated prodrug displays significantly increased cytotoxicity in human cancer cells compared with oxaliplatin, and it is able to kill tumor cells much more efficiently than oxaliplatin in a mouse tumor model. Our work significantly contributes to the development of photoactivatable anticancer prodrugs, especially by red light. We report the design, evaluation, and photoactivation mechanism of phorbiplatin, a platinum(IV) antitumor prodrug that can be controllably activated by red light. Phorbiplatin maintains its integrity without irradiation, but under irradiation with red light, the prodrug is quickly and efficiently activated, releasing oxaliplatin and PPA. The prodrug shows significant antitumor activity both in vitro and in vivo.
Cytotoxicity and ROS production of novel Pt(IV)oxaliplatin derivatives with indole propionic acid
Tolan, Dina,Almotairy, Awatif Rashed Z.,Howe, Orla,Devereux, Michael,Montagner, Diego,Erxleben, Andrea
, p. 262 - 267 (2019)
The coordination of biologically active moieties to the axial positions of Pt(IV)derivatives of Pt(II)anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV)complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV)complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by 1H and 195Pt NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans-[Pt(DACH)(ox)(IPA)(OH)](1), trans-[Pt(DACH)(ox)(IPA)2](2), trans-[Pt(DACH)(ox)(IPA)(bz)](3), trans-[Pt(DACH)(ox)(IPA)(suc)](4), and trans-[Pt(DACH)(ox)(IPA)(ac)](5)(DACH = 1,2-diaminocyclohexane (1R,2R)-(?), ox = oxalate, IPA = indole-3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS)in a time-dependent manner. The most potent ROS producer, complex 1, also elicited the highest cytotoxicity. Complex 1 was shown to form the mono- and bis-adducts [Pt(DACH)(guanosine)(OH)]+ and [Pt(DACH)(guanosine)2]2+ in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA.
Electrodrugs: An electrochemical prodrug activation strategy
Norman, Daniel J.,González-Fernández, Eva,Clavadetscher, Jessica,Tucker, Lulu,Staderini, Matteo,Mount, Andrew R.,Murray, Alan F.,Bradley, Mark
, p. 9242 - 9245 (2018)
The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated.
An intramolecular photoswitch can significantly promote photoactivation of Pt(iv) prodrugs
Chen, Shu,Deng, Zhiqin,Hirao, Hajime,Li, Cai,Wang, Zhigang,Xu, Zoufeng,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
, p. 6536 - 6542 (2021/05/31)
Selective activation of prodrugs at diseased tissue through bioorthogonal catalysis represents an attractive strategy for precision cancer treatment. Achieving efficient prodrug photoactivation in cancer cells, however, remains challenging. Herein, we report two Pt(iv) complexes, designated as rhodaplatins {rhodaplatin 1, [Pt(CBDCA-O,O′)(NH3)2(RhB)OH]; rhodaplatin 2, [Pt(DACH)ox(RhB)(OH)], where CBDCA is cyclobutane-1,1-dicarboxylate, RhB is rhodamine B, DACH is (1R,2R)-1,2-diaminocyclohexane, and ox is oxalate}, that bear an internal photoswitch to realize efficient accumulation, significant co-localization, and subsequent effective photoactivation in cancer cells. Compared with the conventional platform of external photocatalyst plus substrate , rhodaplatins presented up to 4.8 × 104-fold increased photoconversion efficiency in converting inert Pt(iv) prodrugs to active Pt(ii) species under physiological conditions, due to the increased proximity and covalent bond between the photoswitch and Pt(iv) substrate. As a result, rhodaplatins displayed increased photocytotoxicity compared with a mixture of RhB and conventional Pt(iv) compound in cancer cells including Pt-resistant ones. Intriguingly, rhodaplatin 2 efficiently accumulated in the mitochondria and induced apoptosis without causing genomic DNA damage to overcome drug resistance. This work presents a new approach to develop highly effective prodrugs containing intramolecular photoswitches for potential medical applications. This journal is
Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues
Chen, Shu,Gunawan, Yuliana F.,Tse, Man-Kit,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
supporting information, (2020/08/24)
Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.
Anti-tumor platinum (IV) complexes bearing the anti-inflammatory drug naproxen in the axial position
Tolan, Dina A.,Abdel-Monem, Yasser K.,El-Nagar, Mohamed A.
, (2019/01/16)
The role of inflammation in cancer generation is gaining importance in the field of cancer research. The chemo-anti-inflammatory strategy that involves using non-steroidal anti-inflammatory drug compounds as effective anti-tumor agents is being acceded globally. In the present study, seven new Pt (IV) complexes based on cisplatin, carboplatin and oxaliplatin scaffold bearing the anti-inflammatory drug naproxen in the axial position were synthesized and characterized by elemental analysis, ESI-MS, Fourier transform-infrared, 1H- and 195Pt-NMR spectroscopy. The reduction behavior in the presence of ascorbic acid was studied using high-performance liquid chromatography. The cytotoxicity against two human breast cell lines and the anti-inflammatory properties were evaluated. All the complexes are able to promote a comparable activity, with average three- and 13-fold more cytotoxic than cisplatin against MCF7 and MDA-MB-231 cell lines, respectively. The complexes show remarkable anti-inflammatory effects, which indicated their potential in treating cancer associated with inflammation and reducing side-effects of chemotherapy.
An oxaliplatin(iv) prodrug-based supramolecular self-delivery nanocarrier for targeted colorectal cancer treatment
Lim, Wei Qi,Phua, Soo Zeng Fiona,Chen, Hongzhong,Zhao, Yanli
supporting information, p. 12762 - 12765 (2018/12/12)
A redox-responsive supramolecular nanocarrier was constructed from the self-assembly of spermine modified cyclodextrin and oxaliplatin prodrug. The nanocarrier could preferentially accumulate in polyamine transporter over-expressing HCT116 cells, releasing drugs under a reducing intracellular environment to maximize anticancer treatment.
Synthetic method of oxaliplatin
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Paragraph 0012; 018-0020; 0023-0025; 0028-0030, (2017/08/31)
The invention discloses a synthetic method of oxaliplatin. The synthetic method comprises the following steps: firstly, taking potassium chloroplatinite and (1R,2R)-1,2-cyclohexanediamine, putting the substances into water, keeping a mixed solution in dark place and reacting the mixed solution under the conditions that the temperature is 35 to 45 DEG C and microwave is 200 to 500W to obtain cis-dichloro(1R,2R)-1,2-cyclohexanediamineplatinum; secondly, dissolving a product obtained in the first step into water, adding silver sulfate, keeping a mixed solution in the dark place, stirring the mixed solution under the conditions that the temperature is 35 to 50 DEG C and microwave is 200 to 400W and then filtering; thirdly, taking filtrate in the second step, adding tetraethylammonium lodide and activated carbon, stirring and filtering; fourthly, taking filtrate in the third step, first adding oxalic acid and Ba(OH)2.8H2O in the stirring process, stirring for 2 to 3 hours under the condition of keeping in the dark place, filtering, and evaporating and refining the filtrate to obtain the oxaliplatin. By using microwave reaction conditions, the efficiency is improved, reaction time is shortened, production period is shortened, and the production cost is reduced; the purity and the yield of a product are higher.
