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C H Schwalbe

Publications and source records attributed to C H Schwalbe.

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↗
PubMed1991

Structural studies on tazobactam.

Tazobactam (3, C10H12N4O5S) is an effective inhibitor of bacterial beta-lactamases. It crystallizes with unit cell dimensions a = 10.230 (2) A, b = 14.396 (2) A, and c = 17.291 (2) A in space group P2(1)2(1)2(1). Compared to the related inhibitor sulbactam (2), which lacks the triazole ring, crystalline tazobactam exhibits very similar beta-lactam geometry and the same S(1) envelope conformation of the thiazolidine ring. However, in both independent molecules of 3 a triazole ring nitrogen atom accepts an intermolecular hydrogen bond; similar interaction by this moiety of 3 with a hydrogen-bond donor on the enzyme, which is impossible for 2, could account for its enhanced inhibitory power. Semiempirical molecular orbital calculations show pronounced negative potential there. Molecular mechanics supports the hypothesis that the carboxyl group can rotate freely and the triazole ring can "flip".

Computer Simulation↗
PubMed1991

Structural studies on bio-active compounds. Part 18. Crystal structure and molecular modelling of methyl 4-(3-ethyl-3-hydroxymethyltriazen-1-yl) benzoate.

The title compound is an isomer, differing only by the shift of a methyl group, of the anti-cancer agent ethyl 4-(3-hydroxymethyl-3-methyltriazen-1-yl) benzoate; yet its half-life at physiological pH is only one-third as long. It forms crystals with triclinic symmetry, space group P1, and unit cell dimensions a = 6.184 (2), b = 7.214 (2), c = 14.575 (2) A, alpha = 89.61 (2), beta = 79.96 (2), gamma = 68.76 (2)0. Its labile N-CH2OH bond is slightly shorter than that of the more stable isomer but becomes almost equal after optimization of geometry by semi-empirical molecular orbital techniques. Calculated heats of formation are virtually identical for these compounds, as they are for the daughter species after loss of CH2O. The hydroxyl group forms an intermolecular hydrogen bond to a carboxyl oxygen atom in preference to the less negative triazene N(1).

Antineoplastic Agents↗
PubMed1990

Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA.

The structural and electronic properties of the major groove-binding anti-tumour imidazotetrazinones, mitozolomide and temozolomide were studied using molecular orbital techniques. Structure-activity relationships of mitozolomide derivatives emphasized the importance of a hydrogen bond donor on the C8-substituent and showed that good activity would be expected for derivatives carrying a small C8-substituent with restricted negative potential. The coplanarity of the carboxamide substituent in mitozolomide is unlikely to be disrupted by hydrogen bonding in the major groove. Semi-empirical M.O. calculations gave a very high partial positive charge on C4, indicating an enhanced susceptibility to nucleophilic attack leading to ring opening at this position and the formation of a triazene alkylating agent.

Antineoplastic Agents↗
PubMed1990

Structural studies on bio-active compounds. Part XIV. Molecular modelling of the interactions between pentamidine and DNA.

Molecular mechanics modelling was carried out on the antimicrobial aromatic diamidine, pentamidine, bound to the minor groove of several AT-rich DNA octamers. The pentamidine molecule was found to span four base pairs, with its highly charged amidinium groups forming hydrogen bonds to the O2 of thymine or the N3 of adenine, but not to the backbone phosphate groups. The mean binding energy of the pentamidine-DNA complexes was -52 kcal/mol, of the same order as that of berenil-DNA complexes. There was no significant energy difference between those models which contained GC base pairs and those which did not. The presence of bound pentamidine resulted in some distortion of helix geometry involving helix opening towards the minor groove in most cases and a decrease in the number of residues per turn.

Base Sequence↗
PubMed1989

Structural studies on bio-active compounds. Part XV. Structure-activity relationships for pyrimethamine and a series of diaminopyrimidine analogues versus bacterial dihydrofolate reductase.

The phenylpyrimidine derivative pyrimethamine and its congeners inhibit the enzyme dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) and are of interest as antiproliferative agents. In this study the equilibrium conformations of some pyrimethamine derivatives, and their interactions with Escherichia coli dihydrofolate reductase, were investigated using molecular modelling techniques. In each case the phenyl ring avoided coplanarity with the pyrimidine ring and attained a position approximately perpendicular to it, in agreement with crystal structures. A meta substituent could be placed either side of the pyrimidine plane, forming two non-equivalent, slowly interconverting solution conformations. Except for meta-azidopyrimethamine, both conformations of all the inhibitors were able to bind to the active site cleft of the enzyme with the diaminopyrimidine moiety, making the normal pattern of enzyme/inhibitor hydrogen bonds. One such conformation of the meta-azido compound failed to bind because of unacceptable steric clashes, whilst the other showed enhanced binding energy attributable to the occupation of a hydrophobic pocket by the azido group. The enhanced binding of 2,4-diamino-6-ethyl-5-phenylpyrimidine over its 6-methyl analogue was also related to attractive hydrophobic interactions.

Animals↗
PubMed1989

Structure of cycloguanil hydrochloride by neutron diffraction.

4,6-Diamino-1-(p-chlorophenyl)-1,2-dihydro-2,2-dimethyl-s-triazine hydrochloride, C11H15-CIN5+.Cl-, Mr = 288.20, monoclinic, P21/c, a = 8.783 (2), b = 10.267 (2), c = 17.234 (3) A, beta = 115.72 (1) degrees, U = 1400.1 (5) A3, Z = 4, Dx = 1.337 Mg m-3, lambda = 1.15882 (7) A for unit-cell determination and 1.04702 (7) A for collection of intensity data, mu = 0.191 mm-1, T = 15.0 (5) K, final R(F2) = 0.050 and wR(F2) = 0.063 for 3099 independent reflections. Five atoms of the triazine ring are nearly coplanar. The sixth, the quaternary C(2), is displaced from this plane (P1) so that the bond to one of its methyl substituents is nearly perpendicular to P1 while the other methyl substituent lies almost in the plane. The chlorophenyl-ring plane is nearly perpendicular to P1. The heterocycles form cyclic dimers via hydrogen bonds from the 6-amino group to ring atom N(5) of an adjacent molecule. All other N-H units are hydrogen bonded to the Cl- counter ion. The ring is protonated at position N(3).

Chemical Phenomena↗
PubMed1989

Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line.

A series of 2,4-diamino-5-aryl-6-ethylpyrimidines embracing basic substituents in the 5-aryl ring was synthesized and evaluated for inhibitory activity against rat liver dihydrofolate reductase (DHFR). Maximal enzyme inhibition was observed for compounds bearing a benzylamino (19) or N-alkylbenzylamino substituent (29 and 30) in the 4-position of the phenyl ring and a nitro group in the 3-position, the corresponding 3-amino, 3-azido, or unsubstituted analogues proving only weakly active or inactive as DHFR inhibitors. Selected compounds were also screened in vivo against a methotrexate-resistant tumor, the M5076 murine reticulosarcoma, and antitumor activity in general paralleled activity against DHFR, the (3,4-dichlorobenzyl)amino analogue 26 proving the least toxic compound to exhibit significant antitumor activity. The X-ray crystal structure of the ethanesulfonic acid salt of the N-methylbenzylamino compound 29 has been determined to facilitate future molecular modeling studies in this new series of DHFR inhibitors.

Animals↗
PubMed1988

The geometry of N-hydroxymethyl compounds. Part 2: Crystal structures of 1-(4-carbethoxyphenyl)-3-hydroxymethyl-3-methyltriazene, N-hydroxymethylpentamethylmelamine and N-hydroxymethylbenzamide.

Of the three N-hydroxymethyl compounds in the title, the first two have pronounced antineoplastic activity while the latter is biologically inactive. Crystals of the triazene have monoclinic symmetry with a = 8.540(1), b = 6.346(4), c = 22.460(5)A, beta = 98.75(2) degrees, and space group P21/c. The melamine forms disordered crystals of orthorhombic symmetry with a = 11.957(3), b = 17.267(3), c = 5.769(3)A. Of the symmetry elements in the observed space group Pnma, a mirror plane bisects the average molecule, implying that the hydroxymethyl group has equal probability of lying either side of this plane. Crystals of the benzamide show orthorhombic symmetry with a = 10.045(6), b = 7.763(3), c = 19.409(8)A, and space group Pbca. All three compounds are intermediates along biochemical demethylation pathways. The observed N-CH2OH distances, which are 1.469(5), 1.452(4), and 1.438(4)A respectively for the three compounds, correlate with the stability of this bond as measured by half-life. It is suggested that the correct degree of lability is important for biological activity, short strong bonds being too unreactive and excessively long ones being too unstable.

Altretamine↗
PubMed1987

Structural studies on bio-active compounds. Part 9. 2,4-Diamino-6-azidoquinazoline hydrochloride.

C8H7N7.HCl has a formula weight Mr237.7, and crystallizes in space group P21/n with a = 6.498(1), b = 10.333(8), c = 15.406(5) A, beta = 91.72(2) degrees. The final R factor was 0.049 for 1010 unique observed reflections. The azido substituent is almost linear, coplanar with the heterocycle, and parallel to the C(7)-C(6) ring bond. The heterocycle is protonated at N(1) and extensively hydrogen bonded. The 6-azido compound is at least a 100-fold better inhibitor of Escherichia coli dihydrofolate reductase than the analogue lacking the azido group, according to I50 values. Superimposing the quinazoline moiety upon the pteridine ring of the methotrexate-dihydrofolate reductase (E. coli) complex reveals two orientations of the N3 group in which it can fit the enzyme, making van der Waals contacts. Ab initio molecular orbital calculations suggest that one of these conformations, with torsion angle phi = C(5)-C(6)-N(61)-N(62) = -163.8 degrees, is low in energy.

Crystallography↗