Anti-tumour activity compounds

In order to confirm this hypothesis, we synthesized the benzophenanthridines 40a and 40b by reaction of benzyne f22af with the key intermediates 38a and 38b. which were obtained from the corresponding tetralones f39a and 39bf by reaction with methylamine and titanium tetrachloride followed by addition of oxalyl chloride (Ref. 20). In view of our success, we then used the same procedure to prepare 40c and 40d. the precursors of avicine f41af and nitidine (41 bf. the latter of which has considerable anti-tumour activity. Compound 40c was obtained by reaction between 38b and the aryne 22f, and 40d by reaction between 38b and 22b. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Figure 3.116 Platinum compounds studied for possible anti-tumour activity. I, ris-Dichlorodi-ammineplatinum(II) cisplatin, platinol NSC 119875 neoplatin platinex. II, a.s-Diammine(l,l-cyclobutanedicarboxylato)platinum(II) JM-8 paraplatin NSC 241240. Ill, Oxiplatin. IV, Tetraplatin. V, Amminediacetatodichloro(cyclohexylamine)platinum(IV). VI, cis-Dich oro-trans-dihydroxy-cis-bis(isopropylamine)platinum(IV) iproplatin JM-19 CHIP NSC 256927.

The compound Au(dmamp)(02CMe)2 (dmamp = 2-Me2NC6H4) displays some anti-tumour activity and is undergoing tests on its anti-bacterial activity [200]. 

Oxidation of the phenol ring of cannabidiol (73) or cannabinol to a qui-none ring has been shown to afford compounds with anti-tumour activity. However, these compounds do not bind to the CBi receptor and their mechanism of action is unclear [128],... 

We shall now describe the chemistry of those inorganic complexes which are known to have anti-tumour activity in an effort to outline the permutations which such molecules permit and to indicate possible functional modes. We start from the basic observation of Rosenberg (1).Cis [PtCl2 (NH8)d is a very effective anti-tumour drug. Compounds related to it such as trans [PtCl2(NH3)2] are ineffective. Out of a wide range of transition metal complexes tested few have proved to be effective. The successful compounds have certain common features which can be used to circumscribe some of the factors which are probably required for such a drug. 

Optical activity in metal complexes may also arise either if one of the ligands bound to the metal in the first co-ordination sphere is itself optically active or if the complex as a whole lacks a centre of inversion and a plane of symmetry. Thus all octahedral cts-complexes of the tris-or bis-chelate type have two isomeric forms related by a mirror plane, the d- and /-forms. These species have circular dichroism spectra of identical intensities but opposite in sign. The bands in the circular dichroism spectrum are, of course, modified if ligand exchange occurs but they are also exceedingly sensitive to the environment beyond the first co-ordination sphere. This effect has been used to obtain association constants for ion-pair formation. There also exists the possibility that, if such compounds display anti-tumour activity, only one of the mirror isomers will be effective. 

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

Erba E, Bergamaschi D, Ronzoni S, Faretta M, Tavema S, Bonfanti M, et al. Mode of action of thiocoraline, a natural marine compound with anti-tumour activity. Br. J. Cancer. 1999 Jun 80(7) 971-80. 

Terpenes are polymers of the 5-carbon compound isoprene (Figure 1.12) and, as such, generally display properties similar to those of hydrocarbons. Terpenoids are substituted terpenes (i.e. contain additional chemical groups, such as an alcohol, phenols, aldehydes, ketones, etc.). Only a few such substances could be regarded as true drugs. Terpenes, such as limonene, menthol and camphor, form components of various essential oils with pseudo-pharmaceutical uses. A number of these molecules, however, exhibit anti-tumour activity, of which taxol is by far the most important. 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Platinum Compounds with Anti-Tumour Activity.163... 

So far, a group of chemists under S. M. Kupchan at the University of Virginia have been most active in collaborating with this N.C.I. scheme. In addition to many non-alkaloidal compounds, the alkaloids (58)—(62) have been isolated for which some anti-tumour activity is claimed. 

These studies culminated in a comparison of the anti-tumour activity of the complexes. The ruthenium compound was shown to be active at doses of 400 mg/kg. The animal numbers involved are, however, small and it would be unwise to extrapolate further. The dose levels possible for [RuCl2 (DMSO)i ] are noteworthy and indicate a high LD50 for this complex. 

A number of 8-chloro amines have physiological activity, often anti-tumour activity, and compound (26) is one of these. The chlorine atom must come from the alcohol (27) which is clearly an epoxide adduct of amine (28). 

Because of the tumour growth inhibitory activity of 1-ACPC, a number of amino acid derivatives of cycloalkane have been investigated, among them 2-ACPC. Significant anti-tumour activity was exhibited only by compounds closely related to 1-ACPC [178,179]. 

Several alkynes slow some anti-tumour activity, but recently several bacterial compounds (Figure 32) with especially powerful activity have been discovered and all contain an ene-diyne unit (161). 

Cytotoxicity is a necessary, but not sufficient criterion for anti-tumour activity. All of the compounds with strong anti-tumour activity in vivo also have potent cytotoxicity when measured against B16 melanoma in vitro. The converse relationship was not observed, as some highly cytotoxic complexes have limited in vivo efficacy. This relationship demonstrates the importance of in vivo metabolism and animal testing in drug design and development. 

As cisplatin [(H3N)2PtCl2] developed into a clinically important chemotherapy agent, many inorganic chemists were attracted to the structural similarities of gold(iii) and platinum(ii). Both are d metal ions and form square-planar, four-coordinate structures. Sadler s review of anti-tumour activity by compounds of... 

A review on maytansine and maytansinoids gives an account of the source plants, biological activity, and structure-activity relationships of this important anti-tumour-active family of compounds. Synthetic studies on the ansa macro-lides continue apace. Corey has reported the synthesis of a key intermediate, which incorporates most of the left-hand portion of the ring system, by a simple stereospecific route (Scheme 3). The ester (31) [reported in Vol. 9, p. 258] was... 

An important group of compounds is obtained from bis(chloroethyl) aminophosphonic dichloride by reaction with appropriate alcohols (7.122). These compounds, particularly cyclophosphamide (7.122b), will delay or arrest tumour growth. It is thought that the active cytostatic group may be CI-CH2-CH2-, but replacement of Cl by F destroys the anti-tumour activity. 

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