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L R Hughes

Publications and source records attributed to L R Hughes.

27 records · Page 2Linked to original sources
PubMed1989

Thymidylate synthase: a target for anticancer drug design.

N10-Propargyl-5,8-dideazafolic acid (CB3717) has proved to be an interesting recent addition to the spectrum of antifolate drugs. Its sole biochemical locus of action appears to be thymidylate synthase, an inhibitory effect which is potentiated by intracellular polyglutamation. The drug has shown a spectrum of clinical activity and toxicity which is unusual for an antimetabolite. It seems likely that the former is attributable to its inhibition of TS, whilst the latter relates to the drug's poor aqueous solubility at physiological pH. Seminal to the discovery of a new generation of more selective thymidylate synthase inhibitors has been the observation that the C2 desamino derivative (CB3804) retains the useful TS-inhibitory and cytotoxic properties of CB3717. It is some two orders of magnitude more water soluble than CB3717 at physiological pH and appears not to produce, in the mouse, the liver and kidney toxicities which have restricted the wider use of CB3717. Thus, in desamino CB3717, it has proved possible to separate the structural features determining antitumor activity from those which are responsible for its systemic toxicities. These encouraging results prompted systematic structure-activity studies of other C2-modified quinazolines, which revealed that the desirable properties of the desamino compound are not unique. Results with two other CB3717 analogues, the C2-methyl (CB3819) and C2-methoxy (CB3828), have been discussed in the present paper. All three CB3717 analogues exhibit TS-inhibitory activities which are broadly comparable to those of the parent drug. In continuous culture CB3828 is as cytotoxic as CB3717, while CB3804 and CB3819 are at least an order of magnitude more potent. As with the desamino derivative (CB3804), so CB3819 is substantially more water soluble than CB3717 and is apparently devoid of its major toxicities. However, the effects of CB3828 on whole cell TS inhibition, both in vitro and in vivo, are rapidly reversible upon removal of exogenous compound, while the inhibition is sustained in similar experiments with the other three compounds. It is likely that these effects relate to the extent to which the various derivatives are converted to polyglutamate species and retained intracellularly. With the exception of CB3828, all are good substrates for FPGS, and the polyglutamate derivatives of CB3717, CB3804 and CB3819 are better TS inhibitors than the corresponding monoglutamates. CB3804 and CB3819 are less toxic and are cleared from the plasma much more rapidly than CB3717, so that the rate and extent of their polyglutamation may be an essential prerequisite of pharmacological activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Quinazoline antifolate thymidylate synthase inhibitors: nitrogen, oxygen, sulfur, and chlorine substituents in the C2 position.

The synthesis of 16 new N10-propargylquinazoline antifolates with methylamino, ethylamino, (2-aminoethyl)amino, [2-(dimethylamino)ethyl]amino, (2-hydroxyethyl)amino, (carboxymethyl)amino, dimethylamino, imidazol-1-yl, methoxy, ethoxy, phenoxy, 2-methoxyethoxy, 2-hydroxyethoxy, mercapto, methylthio, and chloro substituents at C2 is described. In general, the synthetic route involved the coupling of diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate (5a) with 6-(bromomethyl)-2-chloro-3,4-dihydro-4-oxoquinazoline in N,N-dimethylformamide with calcium carbonate as the base, displacement of the C2-chloro substituent with nitrogen and sulfur nucleophiles, and deprotection using mild alkali. The C2-ether analogues were most conveniently prepared by coupling 5a with 6-(bromomethyl)-2,4-diakoxy(or diphenoxy)quinazolines. In this series the final deprotection step with aqueous alkali gave simultaneous selective hydrolysis of the C4-alkoxy or C4-phenoxy substituent. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). As a measure of cytotoxicity, they were examined for their inhibition of the growth of L1210 cells in culture. The C2-methoxy analogue 11a was equivalent to the previously described tight binding TS inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717, ICI 155387, 1a) against the TS enzyme and exhibited enhanced potency in culture. The C2-methoxy substituent also gave a 110-fold enhancement in aqueous solubility relative to the C2-amine. These results suggest that 11a will be an interesting compound for further study as a potential antitumor agent in vivo. A further series of 2-methoxyquinazoline antifolates with modified alkyl substituents at N10 is also described. None of these analogues equalled the activity of 11a. Thus the propargyl group appears to be the optimum N10 substituent in both 2-amino- and 2-methoxyquinazoline antifolates.

Animals↗
PubMed1976

Colitis associated with oral clindamycin therapy. A clinical study of 16 patients.

The clinical, radiologic, and histologic features of 16 patients hospitalized with clindamycin-associated colitis are presented. The findings are tabulated and compared to 33 cases reported in the literature. The majority of patients were caucasian females over 40 years of age. The clinical presentation varied from mild persistent diarrhea to acute surgical abdomen. Proctoscopic examination revealed nonspecific colitis in 9 and pseudomembranous colitis in 7 cases. No specific radiologic or histologic fingings for postanitbiotic colitis were found. Therapy was nonspecific and varied according to the severity of the clinical course. Clinically, there appeared to be some benefit from systemic steroid therapy. 4 of the 16 patients died. None of the recovered patients have had spontaneous relapses off medication during follow-up evaluation. The pathogenic mechanism for postantibiotic colitis secondary to clindamycin remains unknown and does not appear dose related. Clindamycin therapy should be limited to disorders with specific indications.

Adult↗
PubMedDate not supplied

Nonsteroidal progestins and antiprogestins related to flutamide.

From the dual progestin/antiandrogenic properties of certain synthetic steroids (e.g. cyproterone acetate), it was apparent that the progesterone (P) and androgen (A) receptors must have some common ligand binding features. The nonsteroidal antiandrogen (aA) hydroxyflutamide was therefore considered a possible starting point for medicinal chemistry aimed at antiprogestin (aP) activity. Various modifications to the side chain and aryl ring substituents of flutamide yielded both P and aP activity, but always coupled with varying degrees of A or aA activity. Mineralocorticoid activity was present in some structures, but glucocorticoid and antiglucorticoid activities were not detected. Species (rat, rabbit and monkey) and chiral differences presented formidable difficulties in developing simple structure activity patterns, and low ( < 1%) in vitro uterine receptor binding belied in vivo potency of some aPs. One of the most active aPs, ZM172406, the R enantiomer of ZM150271, N-(3-chloro-4-cyanophenyl)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide, had comparable oral potency to mifepristone in rats and monkeys. The racemate ZM150271 was an effective abortifacient during early pregnancy in pigtailed monkeys (3 x 10 mg/kg) but less effective in cynomolgus monkeys. One of the most active progestins (Pn), ZM182345, N-(4-nitro-3-trifluoromethylphenyl)-4-phenyl-2-hydroxy-2-trifluoromet hyl-pentanamide, was at least as potent as P in rats and rabbits but also possessed A activity.

Abortifacient Agents, Nonsteroidal↗