Second-generation Analogues Research Articles

PT523 and Other Aminopterin Analogs with a Hemiphthaloyi-L­ ornithine Side Chain: Exceptionally Tight-binding Inhibitors of Dihydrofolate Reductase which are Transported by the Reduced Folate Carrier but cannot form Polyglutamates

Abstract: Nonpolyglutamatable antifolates are potentially of therapeutic interest for the treatment of tumors that are inherently refractory or have become resistant, to classical antifolates as a result of decreased expression of the enzyme folylpolyglutamate synthetase. An interesting class of water-soluble nonpolyglutamatable analogs of aminopterin (AMT) have been developed, which are much more cytotoxic because they bind more tightly to dihydrofolate reductase (DHFR) and also utilize the reduced folate carrier (RFC) pathway more efficiently for influx into the cell. This review summarizes the in vitro and in vivo preclinical data on the initial lead compound, Na-(4-amino-4-deoxypteroyi)-N >-hemiphthaloyi-L-ornithine (PT523}. In addition, the synthesis and in vitro biochemical and biological properties of several types of second-generation analogs are discussed. Analogs modified in the B-ring of the pteridine moiety have been found to be of particular interest because their affinity for DHFR and their influx rate into cells via the RFC pathway are even greater than those of PT523. The hemiphthaloylornithine moiety, which is larger and more hydrophobic than the glutamate side chain of classical antifolates, appears to be chiefly responsible for the exceptionally high biological potency of PT523 and its B-ring analogs.

4-Aryldihydropyrimidines via the Biginelli Condensation: Aza-Analogs of Nifedipine-Type Calcium Channel Modulators

Recent results from the author's laboratory in the area of dihydropyrimidine chemistry are summarized.

Consensus statement: Benefits versus risks of medical therapy for acromegaly

A consensus panel defined the risks and benefits of medical management of acromegaly and determined a place for the use of the somatostatin analogue, octreotide, in the overall management strategy of patients with acromegaly. Octreotide was considered effective in managing acromegaly, and its role as an adjuvant to surgery was defined. Octreotide is beneficial to radiotherapy-treated patients in that the drug suppresses growth hormone (GH) secretion until the long-term effects of radiation occur. Complications associated with octreotide are minor relative to the benefits, but requirements for multiple daily injections and drug cost are drawbacks. Approximately 20% to 30% of octreotide-treated acromegalic patients develop gallstones or sludge, which are usually asymptomatic and require no treatment. Surgery continues to be the principal therapeutic approach for GH-secreting pituitary tumors, and improved octreotide delivery methods and second-generation analogues will provide further advantages for pharmacotherapy.

WR2721 as a modulator of cisplatin- and carboplatin-induced side effects in comparison with other chemoprotective agents: a molecular approach.

Cisplatin is an active cytostatic that became successful in the treatment of several types of solid tumours after its nephrotoxic potential was controlled by hydration and diuresis. Thiol compounds were tested to reduce further cisplatin-induced nephrotoxicity. Thiosulphate is rapidly excreted by the kidneys and protects against cisplatin-induced nephrotoxicity by inactivating reactive platinum species in the kidney. Due to inactivation of cisplatin in the circulation, thiosulphate also interferes with its antitumour activity. Therefore, it is mainly used in two-route schedules, whereby cisplatin is delivered locally to the tumour (i.p. or i.a.) while systemic (i.v.) thiosulphate protects the kidneys. Diethyldithiocarbamate was shown to protect against cisplatin-induced nephrotoxicity in several animal models by reversing cellular damage. However, in the clinic it has been less successful, partly due to its central nervous system toxicity. The endogenous thiol compounds glutathione and metallothionein have been shown to reduce cisplatin-induced toxicity both in animal models and in clinical trials. However, the results are rather preliminary and a reduction in therapeutic efficacy may be expected, for both glutathione and metallothionein have been reported to be involved in platinum resistance. The thioether methionine has been shown to reduce cisplatin-induced nephrotoxicity in animal models but it has not yet been tested in the clinic. Cisplatin-induced acute emesis can be sufficiently controlled with a new class of 5-hydroxytryptamine-3 (5HT3)-receptor blockers, but delayed emesis remains a problem. High-dose cisplatin regimens with protection of the kidneys induces ototoxicity, peripheral neuropathy and myelotoxicity, which become dose-limiting. Neurotoxicity was partly reversed by the neurogenerative agent ORG2766, but this agent does not reduce other cisplatin-induced toxicities. Therefore, an agent capable of protecting multiple non-tumour tissues is needed. Carboplatin is a second-generation analogue of cisplatin with less nephro-, neuro- and ototoxicity. Carboplatin is at least as active as cisplatin at its maximum tolerated dose, which is defined by its myelotoxicity. Protection from carboplatin-induced myelotoxicity may be controlled by autologous bone marrow transplantation and/or hematopoietic growth factor infusions. High-dose carboplatin schedules may cause nephrotoxicity, neurotoxicity and ototoxicity. Again, the protection of multiple non-tumour tissues is needed. WR2721 appears to be such a modulating agent capable of protecting multiple non-tumour tissues. It was shown to be preferentially metabolized and taken up as the thiol metabolite WR1065 by non-tumour tissues as compared with (hypoxic) solid tumours. It was shown to protect mice from cisplatin-induced nephrotoxicity and from cisplatin- and carboplatin-induced myelotoxicity without interfering with the antitumour activity.(ABSTRACT TRUNCATED AT 400 WORDS)

The development of a second-generation triazene

The general approach in the search for a second-generation analogue suitable for clinical investigation is usually twofold. One is determination of the mechanism of action of the parent drug and any metabolism this might involve, and the second a structure-activity study aimed at establishing the basic structural requirements of this molecular type for the biological activity of interest. This combined knowledge can then be used to design novel compounds which may improve on the efficacy of the clinical parent. A study of this type requires a ready interaction between chemist, biologist, biochemist, pharmacologist and clinician. Such interactions were involved in the choice of a secondgeneration triazene. DTIC [Ia, R’ = H; 5-(3,3-dimethyl-l-triazeno)imidazole-4-carboxamide, DIC, Dacarbazine] has been available clinically now for some 20 years. Although studied in a variety of tumour types (2), its most significant activity as a single agent is to produce an overall 23% response rate in the treatment of malignant melanoma (3), the highest response rate shown by this disease to any single agent therapy (8). DTIC has been used also in a variety of combination regimens against other tumour types. Inevitably DTIC has drawbacks in terms of its clinical side-effects. Myelosuppression is dose-limiting and severe nausea and vomiting lead to poor patient tolerance. The potential usefulness of the triazenes as a class of compounds, has led a number of groups to look for a second-generation, more clinically useful, analogue. The development of imidazotetrazinones as chemically activated prodrugs (15), at Aston University, and work at the Institute of Cancer Research concentrating on aryl analogues of DTIC, have both led to new drugs being entered into clinical investigations. The reasons for our choice of the aryl series dates back to the available knowledge on the triazenes and DTIC in particular in the early 1970s. DTIC had been developed by Shealy and his colleagues at the Southern Research Institute as a prodrug form of 5diazoimidazole-4-carboxamide (12, 13, 14). Although an inhibitor of the Walker 256 rat carcinosarcoma, 5-diazoimidazole-4-carboxamide is chemically unstable under physiological conditions, undergoing intramolecular cyclization to 2-azahypoxanthine. DTIC is not readily hydrolysed to 5-diazoimidazole-4-carboxamide under normal conditions,