Clinical agents

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

It probable that the above are but the forerunners of an extensive series of clinical agents. 

The key to clinical agents in this series, the secondary amine, 65, is obtained by a sequence analogous to that used to obtain desmethymorphine. Thus, the phenol (63) is first acetyl-ated (64), and then demethylated by treatment with cyanogen bromide hydrolysis gives the desired aminophenol (65). Alkylation... 

Farrell, N. P. Qu, Y. Bierbach, U. Valsecchi, M. Menta, E. Structure-activity Relationships within Di- and Trinuclear Platinum Phase I Clinical Agents In Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug Lippert, B., Ed. Verlag, 1999, pp 479 196. 

Davies, M. S. Thomas, D. S. Hegmans, A. Berners-Price, S. J. Qu,Y. Farrell, N. A Comparison of the kinetics of formation of 1,4-interstrand crosslinks by the trinuclear clinical agent BBR3464 Preassociation and evidence of conformational flexibility J. Am. Chem. Soc. submitted for publication. 

Hardy, L. W. and Malikayil, A. (2003). The impact of structure-guided drug design on clinical agents. Curr. Drug Discov. 3,15-20. 

Alkaloids such as vinblastine and vincristine are known to bind to the microtubules of the spindle apparatus. They are active agents that influence DNA synthesis and amino acid metabolism. They are also known to reduce mitosis at metaphase. Vinblastine and vincristine also have some immunosuppressive activity. There are many applications of these alkaloids. They have been used in the treatment of Hodgkin s disease, cancers and blood disorders. Vincristine is a basis for the development of clinic agents used to treat cerebral and pulmonary disorders. Vinblastine and vincristine are well-known anficancer agents. 

Structure-activity relationships can be inferred by comparison of the antibacterial properties of the clinical agents and related compounds. Different acyl side chains can result In significant changes in the antibacterial activity, both with respect to potency and to breadth of spectrum. The highest activities are observed when the aeylaniino side chain at C-7 is a substituted acetic add. Homologation of the acetic add moiety lowers activity dramatically as exemplified by1 the naturally occurring cephalosporins, which all have weak activity. 

This review summarized our systematic studies on dinuclear platinum compounds leading to identification of a novel clinical agent BBR 3464. The profile of antitumor activity is shared by the general structure with po-... 

Leucovorin or folinic acid, a mixture of the 6R- and 6S,-diastereomers of 5-formyltetrahydrofolic acid, is an important clinical agent which may be used as a remedy for megaloblastic anemia and as an antidote for inadvertent overdosages of antifolates in patients with cancer, parasitic diseases, or autoimmune disorders such as psoriasis and rheumatoid arthritis. In view of these applications it is surprising that few significant improvements in the manufacture of leucovorin have occurred... 

Perhaps the best known clinical agent is the heptaene polyene, amphotericin B 50, isolated from Streptomyces nodosus and first reported in 1956. The full structure was not elucidated until 1970 when it was determined by X-ray crystallography,56 closely followed by a description of the absolute configuration determined by utilising the iodo-derivative for X-ray and by mass spectroscopy.57 Quite recently, 50 years after its initial discovery, a full review giving the highlights of the chemistry around the compound was published by Cereghetti and Carreira.58... 

FR901379 (isolated from the fungus Coleophoma empetri) and echinocandin B (isolated from Aspergillus nidulans) led to two additional clinical agents of this class, micafungin (41) and anidulafungin (42), respectively. (16, 17)... 

After retiring in 1975, he continued active research but moved to a new application of catalytic chemistry. He synthesized new platinum-containing molecules that are derivatives of the same family known as dv-platinum, which was discovered to have antitumor activity. Turkevich s candy-coated cfv-platinum derivatives were also useful clinical agents in cancer chemotherapy. Even at the end of his life, Turkevich was still doing experiments with colleagues in medicine and chemistry. 

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. 

Four caprcomycins. designated lA. IB. IIA. and IIB. have been isolated from cultures of S. capreoliis. The clinical agent contains primarily lA and IB. The close chemical relationship between capreomycins lA and IB and viomycin was established." and the total synthesis and proof of structure of the capreomycins were later accomplished."" The structures of capreomycins IIA and IIB correspond to those of lA and IB but lack the /3-lysyl residue. The sulfate salts are freely. soluble in water. 

Another type of alkylating species occurs in o. unsatu-nicd L urhonyl compounds. These compounds can alkylate nucleophiles by conjugate addition. Although there arc no established clinical agents of this type, many natural products active against experimental tumors contain a-methylcne lactone or er. unsatunitcd ketone functionalities. For... 

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