Qing-Song Ye

Synthesis and anticancer activity of [2-hydroxy-1,3-diaminopropane-κ2N,N'] platinum(II) complexes

A series of novel platinum(II) complexes involving a carrier with HO- peripheral functional group, 2-hydroxy-1,3-propanediamine (HO-pda), cis-[Pt(HO-dpa)X(2)] (X(2)=2Cl(-) (1), C(2)O(4)(2-) (2), malonate (3), 1,1-cyclobutane dicarboxylate (CBDCA) (4), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA) (5)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray diffraction for three representative complexes 1, 4 and 5. The Pt(II) is in a square planar environment and is coordinated in cis position by a chelating HO-pda and 2Cl(-) for 1 and CBDCA for 4 and 5. Pt-N, Pt-Cl and Pt-O distances and coordinate bond angles of N-Pt-N, Cl-Pt-Cl and O-Pt-O are in the normal range. There are two independent molecules in the asymmetric unit of 5, held together by intermolecular hydrogen bonded chain. All the complexes show significant cytotoxicity on the sensitive cell lines SGC-7901, LNcap and A549, and are more active than carboplatin. 4 is also found to be active against the resistant cell A549/ATCC, which suggests that it has less cross-resistance with cisplatin than carboplatin. Moreover 4 shows much greater inhibition of tumor growth than carboplatin in S180-bearing mice, and is therefore worthy of further development as a potential anti-tumor platinum drug.

Two mixed-NH3/amine platinum (II) anticancer complexes featuring a dichloroacetate moiety in the leaving group

Two mixed-NH3/amine platinum (II) complexes of 3-dichoroacetoxylcyclobutane-1, 1-dicarboxylate have been prepared in the present study and characterized by elemental analysis and IR, HPLC-MS and 1H, 13C-NMR. The complexes exist in equilibrium between two position isomeric forms and undergo hydrolysis reaction in aqueous solution, releasing the platinum pharmacophores and dichloroacetate which is a small-molecular cell apoptosis inducer. Both complexes were evaluated for in vitro cytotoxic profile in A549, SGC-7901 and SK-OV-3 caner cells as well as in BEAS-2B normal cells. They exhibit markedly cytoxicity toward cancer cells by selectively inducing the apoptosis of cancer cells, whereas leaving normal cells less affected. They have also the ability to overcome the resistance of SK-OV-3 cancer cells to cisplatin. Our findings offer an alternative novel way to develop platinum drugs which can both overcome the drug resistance and selectively target tumor cells.

A novel water-soluble heptaplatin analogue with improved antitumor activity and reduced toxicity.

A novel water-soluble heptaplatin analogue, cis-[(4R,5R)-4,5-bis-(aminomethyl)-2-isopropyl-1,3-dioxolane](3-hydroxy-1,1-cyclobutanedicarboxylato)platinum(II), has been synthesized and biologically evaluated. The complex shows more activity and less toxicity than its parent drug heptaplatin, exhibiting the great potential for further development.

Synthesis, anticancer activity and toxicity of a water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)}.

A water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)} was synthesized. The anticancer activity and toxicity were evaluated by comparing its interaction with DNA, cytotoxicity against four human cancer cell lines, antitumor efficiency in human gastric carcinoma NCI-N87 xenografts in nude mice, and preliminary side-effects in rats to those of its 4R,5R-optical isomer which is under preclinical development. Both isomers induce condensation of DNA to the same extent and have similar cytotoxicity, but show different antitumor activity and toxicity, probably owing to the difference in respective pharmacokinetic profiles. 4S,5S-Isomer seems to exhibit superior antitumor activity and less toxicity than 4R,5R-optical isomer as well as the parent heptaplatin. These results imply that 4S,5S-configuration as a new drug candidate may be better than 4R,5R-counterpart.

Unusual Dimeric Chemical Structure for a Carboplatin Analogue as a Potential Anticancer Complex

An unexpected and unusual dimeric platinum(II) tetracarboxylate complex was obtained by the reaction of cis-[Pt(NH(3))(2)I(2)] with disilver dicarboxylate. The complex exhibits greater in vitro anticancer activity and lower toxicity in mice than its parent compound, carboplatin, and is therefore worthy of further evaluation as a potential antitumor dinuclear platinum agent.

3-Hydroxycarboplatin, a Simple Carboplatin Derivative Endowed with an Improved Toxicological Profile

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China *Email: liguanglou1@126.com 3-Hydroxycarboplatin, a simple carboplatin derivative, was synthesised using a novel method, characterised and evaluated for its anticancer activity in vitro and in vivo. It shows comparable antitumour activity to that of carboplatin but has much lower toxicity particularly with respect to myelosuppression, revealing great potential for development as a new antitumour platinum drug to replace carboplatin.

Novel Lipophilic Platinum(II) Compounds of Salicylate Derivatives

Canada, Australia and European countries, about 25% of deaths are related to malignant diseases. Chemotherapy is a central component in the fight against cancer. It is based on various classes of compounds, among which platinum-based drugs are a unique class. cis-Diamminedichloroplatinum(II) (cisplatin), first approved for clinical use in 1978 in the U.S.A., is one of the most effective anticancer drugs currently available for the treatment of testicular, lung and bladder carcinomas. Driven by the impressive impact of cisplatin on cancer therapy, numerous analogues have been prepared and evaluated in a search for alternative active agents, leading to the discovery of another important Pt drug, carboplatin, cis-diammine(1,1cyclobutanedicarboxylato)platinum(II) in 1986. Today, carboplatin has become one of the most successful anticancer drugs after cisplatin and has received worldwide approval for treating ovarian and small lung cancers (1, 2). Carboplatin shows a spectrum of activity identical with that of cisplatin, but is much less nephrotoxic and emetic. However carboplatin is not effective in treating cancer cells resistant to cisplatin, possibly due to the same diammine carrier, suggesting that crossresistance exists between the two Pt drugs (3, 4). Therefore, the search for new potent Pt complexes possessing high antitumour activity and lack of cross-resistance continues. The so-called ‘third generation’ Pt drug, oxaliplatin, (trans-1R,2Rcyclohexane-1,2-diamine)oxalatoplatinum(II), was approved in 1999 as the first line therapy for metastatic colorectal cancer in combination with 5-fluoroural. Oxaliplatin has also shown potency in many cancer cell lines, including some cells resistant to cisplatin and carboplatin (5). Further Pt-based drugs, nedaplatin, lobaplatin and eptaplatin, have gained regionally limited approval, respectively, in Japan, China and South Korea, for the treatment of certain kinds of cancers (6). Ptbased drugs currently in clinical use are shown in Figure 1. In the meantime, the rational design of Pt anticancer compounds with specific characteristics has led to the invention of the orally available drugs satraplatin (JM216) and picoplatin (AMD473, a sterically hindered complex), see

Design, synthesis and anticancer activity of diam(m)ine platinum(II) complexes bearing a small-molecular cell apoptosis inducer dichloroacetate

Four new diam(m)ine platinum complexes containing the dichloroacetate moiety in 3-dichoroacetoxylcyclobutane-1,1-dicarboxylate as the leaving group were synthesized, characterized by elemental analysis as well as by ESI(+)-MS (electrospray ionization mass spectrometry in positive mode), FT-IR, (1)H- and (13)C-NMR, and evaluated for their in vitro anticancer activity against human lung cancer cell line (A549) and ovarian cancer cell lines (SK-OV-3, SK-OV-3/DDP). Diam(m)ines used in the present study belong to the carriers of six clinically approved platinum drugs. Among the complexes synthesized, complex 2, cis-[Pt(II)(1R,2R-diaminocyclohexane)·(3-dichoroacetoxylcyclobutane-1,1-dicarboxylate)] is the most promising in terms of water solubility and potential of being totally devoid of cross-drug resistance with cisplatin. Therefore, complex 2 was selected for the dichloroacetate release test. The test shows dichloroacetate can be efficiently released from complex 2 under physiological conditions via the hydrolysis of an ester bond bridging the dichloroacetate moiety and platinum pharmacophores together. Our study supports the further evaluation of this complex as a drug candidate.

Synthesis and cytotoxicity of platinum(II) complexes of a physiologically active carrier histamine.

A series of novel platinum(II) complexes involving a physiologically active carrier histamine as the carrier, cis‐[Pt(histamine)X2] (X2 = 2Cl–, oxalate, malonate, 1,1‐cyclobutanedicarboxylate (CBDCA), 3‐hydroxy‐1,1‐cyclobutanedicarboxylate (HO‐CBDCA)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X‐ray crystal structure for a representative complex cis‐[Pt(histamine)Cl2]. The cytotoxicity of the complexes has also been assessed in the human cancer cell lines A549/ATCC, HT‐29, and LNcap. One complex, cis‐[Pt(histamine)Cl2], is more active than carboplatin against both the sensitive and resistant cells.

cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)], a Water-Soluble, Oxalate-Free and Stable Analogue of Oxaliplatin: Synthesis, Characterization, and Biological Evaluations

Oxaliplatin, developed by Kidani et al. , is a third-generation platinum antitumor drug following cisplatin and carboplatin, and has been used worldwide in combination chemotherapeutic treatments of metastatic colorectal cancer. Oxaliplatin is also currently being explored for its potential as a treatment option after failure of cisplatin or carboplatin therapy, owing to its activity in cisplatin-resistant tumor models. Oxaliplatin differs from carboplatin importantly in that two ammine groups of the latter are replaced by (1R,2R)-diaminocyclohexane (DACH), which is largely credited for the unique anticancer properties of oxaliplatin. However, the efficacy of oxaliplatin is