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Biomedical subjects

M F Stevens

Publications and source records attributed to M F Stevens.

At least 19 recordsLinked to original sources
PubMed1992

Antitumor imidazotetrazines. 25. Crystal structure of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) and structural comparisons with the related drugs mitozolomide and DTIC.

The antitumor imidazotetrazinone, temozolomide (5), C6H6N6O2, forms crystals with unit cell dimensions a = 17.332 (3), b = 7.351 (2), c = 13.247 (1), beta = 109.56 (1) degree and space group P21/c. A doubly hydrogen-bonded dimer constitutes the asymmetric unit. One carboxamide group forms an additional intermolecular NH...O hydrogen bond; in both molecules the carboxamide group is coplanar with the heterocycle and its NH2 group interacts with the imidazole nitrogen atom N(7). Molecular orbital calculations show the carbonyl carbon C(4) to be the most electron deficient atom, with relatively weak N(3)-C(4) and C(4)-N(5) bonds confirming that temozolomide should ring-open at this position in solution. The energy barrier to carboxamide group rotation of approximately 20 kJ mol-1 should permit interconversion between rotamers. In temozolomide and the related drug mitozolomide (4), N(7) is more negatively charged than N(1), which favors the formation of hydrogen bonds to the former atom in spite of their poor geometry. The relevance of these structural features to the action of temozolomide as a major-groove-directed prodrug of the alkylating agent MTIC (3) is discussed.

Antineoplastic Agents↗
PubMed1992

Structural studies on bio-active compounds. 20. Molecular modeling and crystallographic studies on methylbenzoprim, a potent inhibitor of dihydrofolate reductase.

Methylbenzoprim (MBP) is a potent inhibitor of dihydrofolate reductase, which is more selective for mammalian than bacterial enzymes. Crystal-structure studies on the free base of MBP, with two independent molecules, and the ethanesulfonate salt, have demonstrated three significantly different conformations for MBP. With the MOPAC optimized MBP cation as starting point, the COSMIC energy was monitored as torsion angles were changed in 5 degrees increments. The barrier to rotation about C(5)-C(11) can create two slowly interconverting rotamers, in agreement with NMR studies. Two conformations of the cation that fit the human DHFR structure from the Brookhaven Protein Data Bank have been found. They differ chiefly by a half-turn about C(5)-C(11), positioning the nitro group on opposite sides but allowing the central and benzylic rings to find hydrophobic surroundings. The central ring is close enough to the predicted position of the cofactor NADPH to make competition likely. Kinetic studies with rat liver DHFR show that MBP is an inhibitor that competes with NADPH as well as dihydrofolate.

Binding Sites↗
PubMed1992

Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856).

Temozolomide (CCRG 81045: M&B 39831: NSC 362856) is an analogue of mitozolomide displaying similar broad spectrum activity in mouse tumours, but showing considerably less myelosuppression in the toxicology screen. Temozolomide was initially studied intravenously at doses between 50-200 mg m-2 and subsequently was given orally up to 1,200 mg m-2. A total of 51 patients were entered on the single dose schedule. Temozolomide exhibits linear pharmacokinetics with increasing dose. Myelotoxicity was dose limiting. Experimentally, temozolomide activity was schedule dependent and therefore oral administration was studied as a daily x 5 schedule between total doses of 750 and 1,200 mg m-2 in 42 patients. Myelosuppression was again dose limiting. The recommended dose for Phase II trials is 150 mg m-2 po for 5 days (total dose 750 mg m-2) for the first course, and if no major myelosuppression is detected on day 22 of the 4 week cycle, the subsequent courses can be given at 200 mg m-2 for 5 days (total dose 1 g m-2) on a 4 week cycle. Mild to moderate nausea and vomiting was dose related but readily controlled with antiemetics. Clinical activity was detected using the 5 day schedule in four (2CR, 2PR; 17%) out of 23 patients with melanoma and in one patient with mycosis fungoides (CR lasting 7 months). Two patients with recurrent high grade gliomas have also had partial responses. Temozolomide is easy to use clinically and generally well tolerated. In the extended Phase I trial temozolomide only occasionally exhibited the unpredictable myelosuppression seen with mitozolomide.

Adult↗
PubMed1992

Structural studies on bio-active compounds. Part 21. Acid-promoted debenzylations in antitumour 2,4-diamino-5-[4-(N-alkylbenzylamino)-3-nitrophenyl]-6-ethylp yrimidines.

Methylbenzoprim and ethylbenzoprim undergo debenzylation in hydrochloric acid. Two reaction mechanisms are proposed to explain this reaction, both of which involve a neighbouring group participation by the nitro group ortho to the tertiary amine fragment. The physical stability of dihydrofolate reductase inhibitors in the benzoprim class may influence the choice of a clinical candidate.

Aniline Compounds↗
PubMed1990

NMR studies of multiple conformations in complexes of Lactobacillus casei dihydrofolate reductase with analogues of pyrimethamine.

1H and 19F NMR signals from bound ligands have been assigned in one- and two-dimensional NMR spectra of complexes of Lactobacillus casei dihydrofolate reductase with various pyrimethamine analogues (including pyrimethamine [1, 2,4-diamino-5-(4'-chlorophenyl)-6-ethylpyrimidine], fluoropyrimethamine [2, 2,4-diamino-5-(4'-fluorophenyl)-6-ethylpyrimidine], fluoronitropyrimethamine [3, 2,4-diamino-5-(4'-fluoro-3'-nitrophenyl) -6-ethylpyrimidine], and methylbenzoprim [4, 2,4-diamino-5-[4'- (methylbenzylamino)-3'-nitrophenyl]-6-ethylpyrimidine]). The signals were identified mainly by correlating signals from bound and free ligands by using 2D exchange experiments. Analogues (such as 1 and 2) with symmetrically substituted phenyl rings give rise to 1H signals from four nonequivalent aromatic protons, clearly indicating the presence of hindered rotation about the pyrimidine-phenyl bond. Analogues containing asymmetrically substituted aromatic rings (such as 3 and 4) exist as mixtures of two rotational isomers (an enantiomeric pair) because of this hindered rotation and the NMR spectra revealed that both isomers (forms A and B) bind to the enzyme with comparable, though unequal, binding energies. In this case two complete sets of bound proton signals were observed. The phenyl ring protons in each of the two forms experience essentially the same protein environment (same shielding) as that experienced by the corresponding protons in bound pyrimethamine: this confirms that forms A and B correspond to two rotational isomers resulting from approximately 180 degrees rotation about the pyrimidine-phenyl bond, with the 2,4-diaminopyrimidine ring being bound similarly in both forms. The relative orientations of the two forms have been determined from NOE through-space connections between protons on the ligand and protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1979

Analysis of ECG data, for data compression.

A number of papers on the subject of data reduction techniques applied to ECG Data have recently been published; however, the authors found that most of these articles did not consider quantization techniques, which can be effectively applied to ECG data without any complex parameter extraction procedures. In this paper the authors have looked at the effects of quantization on ECG data and techniques of reducing the amount of data needed to represent these signals. Basically, 3 data reduction techniques, linear prediction using differential pulse code modulation, spectral analysis and slope change detection are investigated and a relative assessment of their performance is presented. This analysis revealed that a slope change detection, as applied to prefiltered data, can be used to represent ECG data at a rate of 2 bits/sample, while maintaining the mean squared error and peak error below 1% and 5% respectively. This technique therefore gives an effective 3 to 1 reduction over the original sampled data, since it was found that the original data could be quantized to 6 bits without significant loss of waveform information.

Electrocardiography↗