A Crystallographic Study of some Biologically Important Compounds

Abstract

Single crystal X-ray structure determinations are reported for eleven compounds, each of which is either biologically active or potentially biologically important. The compounds fall into four distinct classes: 1. Stable salts of benzylpenicillin 2. Analogues of folic acid and folate antagonists 3. Nucleoside base analogues 4. Novel bicyclic antitumour agents. A common theme throughout the investigation is the nature, importance and possible implications of the hydrogen bonds formed in each of the compounds; the biological importance and/or medicinal interest in each of the above classes is discussed and related to the structures of the individual compounds. Procaine penicillin G and benethamine penicillin G are stable salts of benzylpenicillin, administered as repository drugs in aqueous crystalline suspensions. Their stability to aqueous environments is related to their crystal structures. Because of the importance of folic acid as a target for chemotherapy, a number of analogues and antagonists have been synthesised at Aston. The structures of two such compounds, one a 2:4-diaminopyrimidine, the other a 2-amino-4-oxopyrimidine, are discussed in Chapter 4, paying particular interest to base pair type interactions, interactions with counter ions and solvent molecules, and the geometry of the pyrimidine ring. The structure of a sulphonamide is also reported in an attempt to correlate this with its microbiological properties. The structures of the nucleoside base analogues 6-phenyl-5-azauracil, 6-benzyl-5-azauracil, and 6-methylisocytosine have been determined in order to confirm: a) the tautomeric form in each case, b) to determine the nature of hydrogen bond interactions involved, particularly the type of base pair formation which is dependent upon the order of proton donors and acceptors on the heterocyclic ring, c) to determine in the case of the diketo compounds whether the two carbonyl stretching frequencies observed in the infrared spectrum are due to non-equivalence or vibrational coupling. The structures of mitozolomide (a novel bicyclic antitumour agent developed at Aston University) and two of its analogues are discussed, not only to provide unequivocal proof of the structures but also to provide additional information which may assist in determining the possible modes of action. The structures are compared with those of known similar antitumour agents, e.g., DTIC and DCTIC (see list of abbreviations). The crystallographic software at Aston and Manchester (UMRCC) is reviewed.