Antitumour activity agents

Ferlini C, Distefano M, Pignatelli F, et al. Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors. BrJ Cancer 2000 83(12) 1762-1768. 

From the biochemical point of view, the unique mode of action of some of the ansamycins, in particular of rifampicin, has aroused much interest. Rifampicin and several other ansamycins have been shown to inhibit bacterial transcription very specifically and at extremely low concentrations by interacting exclusively with DNA-dependent RNA polymerase. This unique action has spurred many investigations on the effects of ansamycins in a variety of viral and eukaryotic systems. More recently maytansine and related compounds have been found to be very potent antimitotic agents and to have interesting antitumour activities. 

One of the mildest methods for preparing methylene acetals involves reaction of a diol with dimethoxymethane in the presence of a suitable activating agent such as phosphorus pentoxide,176 trimethylsilyl Inflate.177 or lithium bromide and p-toluenesulfonic acid.178 The reaction is also used to make methoxymethyl ethers (see section 4.4,1) from alcohols. Scheme 3,95 illustrates the simultaneous formation of a methoxymethyl ether and a methylene acetal from Shikimic Acid.169 The reaction was adapted to the synthesis of the methylene acetal moiety of the marine antitumour agent Mycalamide B [Scheme 3.96],179... 

Numerous azido-substituted nucleosides have been evaluated as potential antitumour agents. De Clercq et al. found that of a series of 2 - and 3 -azidonucleoside analogues prepared and evaluated for antitumour activity against murine LI210 cells in vitro, the most potent derivative was 3 -azido-2, 3 -dideoxyadenosine (146), with 3 -azido-2, 3 -dideoxyguanosine (102), 3 -azido-3 -deoxyadenosine (147) and 2 -azido-2 -deoxycytidine (148) proving moderately active [170], the activity of the last compound having been reported previously [171, 172], AZT was also evaluated in this study... 

The anti-neoplastic activity of podophyllotoxin and derivatives has prompted continuous development into clinical agents for treatment of human neoplasia. The semi-synthetic 4 -demethylepipodophyllotoxin derivatives, Etoposide (139) and Teniposide (140). developed by a Sandoz (Basel) group have attracted considerable attention (135-137) (Scheme 28). They have established antitumour activity with lesser toxicity and mechanism of action differing from podophylloxin itself. 

Biologically active platinum complexes, which cross-link defined regions of DNA in cells, possess antitumour activity, and these are evaluated in Chapter 4. In Chapter 5, the present status of the medicinal uses of Cannabis is discussed, particularly as two cannabinoids are now official drugs. The latest methods of treating insulin-resistant diabetic patients with hypoglycaemic agents which do not act by increasing insulin release are described in Chapter 6. 

In the following years, alkylating agents, antimetabolites and a few compounds belonging to other groups were developed which showed antitumour activity and some of which attained clinical importance in the chemotherapy of cancer. 

Widespread reports indicate that, in addition to their anti-inflammatory role, triterpenes have other activities. Triterpenoids have been found to possess cytotoxic, antimicrobial and interesting effects on metabolism. Triterpenoids with antitumour activity include oleanane, lanostane, lupane, friedelane, hopane and quassionoid types. Glycyrrhetinic acid has been described as an antiviral, hypolipidemic and anti-atherosclerotic agent. Cucurbitacins B and E, and oleanolic acid possess a potent protective action on the liver, and ganoderic acid and its derivatives have been shown to be inhibitors of cholesterol biosynthesis. Lanostane derivatives, like suberosol, have also been found to inhibit HIV replication in H9 lymphocytes [1,3]. 

Some natural products contain an aziridine ring, e.g. mitomycins (3 mitomycin C). This is responsible for the cytostatic and antitumour activity of these antibiotics. Many synthetic aziridines have been screened for their antitumour activity. Some have reached the clinic, especially as antileukaemic agents, e.g. 4 and 5. 

D.E.V. Wilman and T.A. Connors, Molecular stucture and antitumour activity of alkylating agents, in Molecular Aspects of Anti-Cancer Drug Action, S. Neidle and M.J. Waring (eds.), MacMillan Press, London, 1983, p. 233. 

Gianasi E, Wasil M, Evagorou EG, Keddle A, Wilson G, Duncan R. HPMA copolymer platinates as novel antitumor agents in vitro properties, pharmacokinetics and antitumour activity in vivo. Eur J Cancer 1999 35 994-1002. 

Lin X, Zhang Q, Rice Jr, Stewart DR, Nowotnik DP, Howell SB. Improved targeting of platinum chemotherapeutics the antitumour activity of HPMA copolymer platinum agent... 

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