Leslie Richard Hughes

Wittig reactions on unprotected aldohexoses: Formation of optically active tetrahydrofurans and tetrahydropyrans

Abstract The addition of phosphonate-sulphone (1) to a series of pyranoses gives either five- or six-membered ring closed sulphones (e.g. (4) or (5)).

Synthetic studies on ambruticin: Determination of the absolute stereochemistry by a chiral synthesis of the cyclopropane ring

Abstract We report the highly stereoselective synthesis of the cyclopropane (3) and its conversion to a degradation product of ambruticin.

Raltitrexed (TomudexTM), a Highly Polyglutamatable Antifolate Thymidylate Synthase Inhibitor

Folic acid has, over the past 50 yr, formed the basis of an enormous amount of medicinal chemistry aimed at finding improved anticancer agents. This stemmed from the discovery of aminopterin (AMT) and methotrexate (MTX) in the late 1940s. Several years after their discovery, they were shown to exert their antitumor activity via the inhibition of dihydrofolate reductase (DHFR). MTX is still widely prescribed today for the treatment of a number of solid tumors and leukemias (see Chapter 3). Over the last decade there has been a resurgence in the number of folic acid analogs entering clinical studies that has resulted from the knowledge that a number of key enzymic reactions in the de novo biosynthesis of nucleotides depend on folate cofactors. The cellular and in vivo pharmacology of MTX and some of its more recent analogs have been very well described in the literature and has formed a platform of knowledge for the development of the antifolate thymidylate synthase (TS) inhibitors over the last 20 yr (see Chapter 1). For example, it was shown that the cytotoxicity induced by the indirect inhibition of TS by MTX may be antagonized by its inhibitory effects on de novo purine synthesis (1). The antipurine effects of MTX were also believed to contribute to the drug-induced gut toxicity in mice (2). These and other data, particularly that relating to 5-fluorouracil (5FU) metabolism and activity, argued that specific folate-based inhibitors of TS may prove to be better drugs (3). Furthermore, ground-breaking research on other aspects of MTX action including drug resistance and polyglutamation substantially contributed to the acceleration of the development of TS inhibitors from basic concept through to clinical evaluation. Indeed several of the early dual inhibitors of DHFR and TS were 5,8-dideaza (quinazoline) analogs of MTX (see Subheading 2.1.). This chapter focuses on reviewing the medicinal chemistry path from these early compounds to the selection of Tomudex (Raltitrexed; ZD1694; Fig. 1) for clinical study. Additionally, a summary is provided of the current state of knowledge regarding the cellular and in vivo pharmacology of the drug. Readers are also advised of a recent review that may provide more detailed information on certain aspects of development (3).

The synthesis of optically active tetrahydropyrans by the addition of a stabilised Witting reagent to pyranose sugars

The addition of the phosphonate–sulphone (8) to the carbohydrates (9) and (10) gave the tetrehydropyrans (11) and (12) as mixtures of α- and β-isomers; treatment of the mixture with sodium hydride gave the purer β-isomers.