Anticancer drugs, and the

A large variety of organotin carboxylates have been prepared, and their structures determined by X-ray diffraction. Part of the impetus for this work has been the search for anticancer drugs, and the aim of relating activity to structure. The early work on structure has been thoroughly reviewed,346 as well as recent developments,347 including the structural work on the organotin derivatives of amino acids and peptides.348... 

It may be of some value to describe, briefly, the early history of the discovery of this class of anticancer drugs and the subsequent tortuous developments leading to its clinical use. 

Efforts to promote medical applications of liposomes have permitted the development of several new drug formulations applicable to a broad range of therapeutics. One of the main areas of liposomes application is cancer therapy, A great number of scientists worldwide have focused their work on drug discovery or the improvement of the efficacy and reduction of the toxicity of known drugs. Two of the main problems in cancer chemotherapy are the toxicity of the known anticancer drugs and the multi drug resistance of certain cancer cells. 

Chitin has been used in columns to isolate pure lectins and determine their structure [94], Chitin and 6-O-carboxymethylchitin activate peritoneal macrophages in vivo, suppress the growth of tumour cells in mice and stimulate nonspecific host resistance against Escherichia Coli infection [95]. Chitin is used for biological activity as mentioned previously oligomers were claimed as anticancer drug and the DP = 5 is active to control the photosynthesis of maize and soybean [96]. 

The limited water-solubility of taxol, coupled with its limited availability in Nature, almost doomed the development of taxol as an anticancer drug, and the fact that it was developed at all is a tribute the... 

We are interested here in covering some of the most important currently used, and new, anticancer drugs and the adverse/hypersensitivity reactions they elicit. 

Tetrahedral Pt derivatives are well-known anticancer drugs and the active complex is generated by ligand solvation, as indicated on the model compound 13 at 600-740 nm (Scheme 9.4) [26]. 

In spite of the fact that few cycloalkynes occur naturally, they gained recent attention when it was discovered that some of them hold promise as anticancer drugs. (See the boxed essay Natural and Designed Enediyne Antibiotics following this section.)... 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

Wijnholds J, Evers R, van Leusden MR, Mol CA, Zaman GJ, Mayer U et al. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nature Med 1997 ... 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

In 1965 Rosenberg et al. (8, 9) accidentally discovered the antiproliferative effect of cis-diammine platinum complexes, which led to the first clinical trials of cis-[PtCl2(NH3)2] 1 in 1971 and resulted in the clinical use of cisplatin worldwide. Cisplatin and carboplatin 2 are the most widely used anticancer drugs, and two other analogs, nedaplatin 3 and oxaliplatin 4 (chiral centers indicated), have recently been approved for clinical use in Japan and France, respectively. 

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