Use as antitumor drugs

The selectivity of P NMR spectroscopy affords a very useful method of analyzing the different types of cyclic phosphamides [9] Figure 6-14 and their metabolites in urine. The pharmaco- kinetics also can be checked by P NMR spectroscopy [10], Cyclic phosphamides (CP) arc used as antitumor drug [11]. These are available as racemic mixtures of enantiomers. By the use of a-, B- and y-cyclodextrins as chiral shift reagents, the determination of the stereochemistry of the three most used drugs cyclophosphamide, trofosphamide and ifosphamide is possible by P NMR spectroscopy. In addition it is shown that cyclophosphamide in human urine is a racemic mixture [10]. 

To date, around 20 000 articles on platinum complexes have been published an excellent approach to the subject can be found in the book by lippert [48], and overviews of metal antitumor agents can be found in the publications of Keppler [49], Sadler [50] or Clarke [51]. Despite this huge volume of work, the only inorganic complexes approved for clinical use as antitumor drugs are dsplatin, 8, carhoplatin, 9, nedaplatin, 10, and oxaliplatin, 11 (colorectal cancer) (Scheme 1.6). Several others are in clinical testing, and the mechanism of action has been examined [52]. 

Zhou et al. described the synthesis of pH-sensitive biodegradable PUs. They used a novel pH-sensitive macrodiol containing acid-cleavable hydrazone linkers, poly(E-caprolactone)-hydrazone-poly(ethylene glycol)-hydiazone- ly(E-caprolactone) diol (PCL-Hyd-PEG-Hyd-PCL). The macrodiol was used with L-lysine ethyl ester diisocyanate (LDI) and L-lysine-derived tripeptide as chain extender [47]. These PUs could self-assemble into micelles in aqneons solutions. Later, the same research group synthesized pH-sensitive polymers nsing 1,4-bntanediol as chain extenders and suggested its use as antitumor drug carriers [41]. 

Two milestones in chemistry may be addressed to the geometric isomers of diamminedichloroplatinum(II). About 100 years ago Alfred Werner laid down the principles of modem coordination chemistry with the help of isomeric [PtCl2(NH3)2] [1]. About 70 years later Barnett Rosenberg and co-workers discovered that the cis isomer is antitumor active, whereas the trans isomer is not [2,3]. Today m-[PtCl2(NH3)2] (cisplatin) is routinely used as a drug, particularly effective against testicular and ovarian cancer [4],... 

An example of genetic susceptibility to toxic effects of a drug is provided by mercaptopurine drugs, such as 6-mercaptopurine, used as antitumor agents. The active forms of these drugs are the methylated metabolites, as shown for the methylation of 6-mercaptopurine in Reaction 8.6.1 ... 

B2S, H6, T8) have been used as antitumor agents. Similarly, the GST substrate ethacrynic acid has been of value in enhancing the cytotoxicity of anticancer drugs in resistant cell lines (T8). Buthionine sulfoximine, an inhibitor of GSH synthesis (Fig. 16) (G12) has been found to be able to resensitize resistant cells to anticancer drugs (B27, S34). 

An improvement of medical devices based on bacterial polymers by the encapsulation of different drugs, opens up the wide prospects in applications for these new devices with pharmacological activity in medicine. PHB polymer was used as a drug delivery matrix for sustaining the release of various drugs such as dipyridamole [DP], indomethacin and antibiotics (rifampicin, metronidazole, ciprofloxacin, levofloxacin), anti-inflammatory drugs (flurbiprofen, dexamethasone, prednisolone), and antitumor drugs (paclitaxel) [132]. 

Streptonigrin was shown to be clinically useful as an antitumor agent but its use as a drug in cancer chemotherapy was hampered due to severe bone marrow depression. Many analogues were made with the sole objective of arriving at a better drug with high anti-tumor activity and low toxicity. Structure activity studies and its mechanism of cytotoxicity have been well documented. Further, its biosynthetic pathways have been established [7-12]. 

Divinyl ether-maleic anhydride [DIVEMA] is a water-soluble polymer that has antitumor activity against various types of tumors. The biological activities of DIVEMA are due to its ability to activate immunocompetent macrophages and natural killer cells. DIVEMA may be used as a drug carrier for superoxide... 

---