Paul C. Hydes

Anti-tumour platinum complexes : relationships between chemical properties and activity

Since the initi, al d i scovery by Rosenberg and Van Camp of po ten t an t i tumour ac t iv i ty in certa in p l a t i n u m amine complexes , ave have been c a r r y i n g out a p r o g r a m m e of synthes is and testing of a w i d e range of these compounds [1-4]. These s tudies have been c a r r i e d out in conjunct ion w i th a number of ins t i tu t ions in the U.K. as i n d i c a t e d in the acknowledgemen t s ~t the end of the p a p e r [5]. P l a t i num complexes of the type [Pt A S X 2] (A z = two monoden ta t e or one b identare amine ] igand ; X2 = two monoden ta te or one b iden ta te an ion ic l igand) genera ted w i d e s p r e a d r e sea rch in teres t and severa l o ther s t ruc tureac t iv i ty s tudies have been r e p o r t e d [7, 8].

Advances in platinum cancer chemotherapy

In the past 4 years substantial progress has been made in the development of platinum cancer chemotherapy. A number of drug candidates have undergone clinical trials and one ‘second generation’ platinum drug, carboplatin, has been approved for use in the treatment of ovarian and small cell lung cancer. This review covers the major developments since the last international conference on Platinum Chemotherapy in Vermont, and attempts to highlight the primary factors that appear to be influencing the synthesis and screening of potential third generation platinum drugs.A predominant feature in the evaluation of analogues has been the emphasis on chelating diamine complexes, in particular those of diaminocyclohexane, which show activity in L1210 tumours that are resistant to cisplatin, and the use of a wide range of carboxylate ligands as a means of circumventing solubility and toxicity problems inherent in the parent compounds. There has also been an increased effort in studies relating to complexes containing mixed amines and functionalised amines, building on the assumption, which remains valid to date, that two amines are a necessary requirement for anti-tumour activity. Efforts have also been made to address the use of complexes containing biologically active ligands, and the concept of targeting compounds to specific organs and formulating drugs to achieve more specific activity or controlled release of drugs with lower toxicities. These may provide a viable route to drugs that can be administered more easily, for example by an oral route, or show a different spectrum of activity. However, it may prove difficult to adequately characterise these more complex systems.The major problem encountered in evaluating cisplatin analogues, as with other prospective cancer drugs, is finding reproducible anti-tumour screens that are predictive of the behaviour of the drugs in the clinic. Progress is being made in the development of sensitive and resistant human tumour xenograft lines and this area should be monitored with interest, as it may provide a key to the development of a future platinum drug, hopefully with a wider range of activity than either cisplatin or carboplatin.

ANTITUMOR PLATINUM COMPLEXES: STRUCTURE-ACTIVITY RELATIONSHIPS

Publisher Summary This chapter presents the major features of the structure–activity studies and discusses some of the known chemical and physical properties of these analogs that are potential second-generation platinum drugs. A large number of platinum complexes have been synthesized and tested for antitumor activity since the initial discovery of such activity in certain platinum amine compounds. Although the structure–activity relationships for Pt (II) and Pt (IV) complexes are still only imprecisely defined, a number of promising analogs are undergoing, or are about to enter, clinical trials. There is evidence from animal work to suggest that less toxic drugs could well emerge. The chances of finding improved activity or spectrum of action are less clear from work to date and must await the phase I human studies. Although several of the compounds have undesirable physical and chemical properties, the next Pt drug will be largely determined by clinical performance.

The sulphito complexes of gold

A new nitro-sulphito gold electrolyte has advantages over available commercial sulphito electrolytes in terms of stability, simplicity of control and the minimum non-porous deposit thickness. In describing its development, the authors review what is known of gold sulphite complexes and their use in gold plating baths.

Studies on transition-metal oxo- and nitrido-complexes. Part 3. Complexes of osmium tetraoxide with tertiary amines, and their reactions with alkenes

Osmium tetraoxide reacts with multidentate tertiaryamines to give L·2OsO4(L = hexamethylenetetramine, 1,4-diazabicyclo[2.2.2]octane, pyrazine, or 5-methylpyrimidine) and with other amines to give L·OsO4(L = quinuclidine, isoquinoline, phthalazine, or pyridazine). Reactions of these adducts with monoalkenes R give the oxo-osmium(VI) esters L·[OsO2(O2R)](L = hexamethylenetetramine, quinuclidine, isoquinoline, or phthalazine) and L·2[OsO2( O2R)](L = 1,4-diazabicyclo[2.2.2]octane). The structures of these compounds are discussed.