Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines.

This report describes the discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". These agents are notable for their activity against a broad spectrum of tetracycline-susceptible and -resistant Gram-negative and Gram-positive aerobic and anaerobic bacteria possessing various classes of tetracycline-resistant determinants [tet B (efflux), tet M (ribosomal protection)]. The design and synthesis of a number of 7-substituted 9-substituted-amido 6-demethyl-6-deoxytetracyclines are described.

A new family of water-soluble, third generation antitumor platinum complexes.

[1,1-Cyclobutanedicarboxylato(2)-O,O'](1,3-dioxane-5,5-dimethan amine- N,N')platinum(II), 3a, a third generation, very water-soluble platinum complex, has been synthesized along with several of its analogues. All members of the new family contain a 1,3-dioxane or 1,3-dioxolane-1,3-diamine as their basic ligand, a moiety which contributes to their increased water solubility, and a bidentate acid ligand, which is responsible for their good stability. They were all easily crystallized and characterized by 1H NMR and elemental analysis, and the parent complex 3a was further characterized by 13C NMR. Their very desirable physical properties combined with their broad spectrum of antitumor activity and reduced toxicity make them good candidates of further development.

Water-soluble third generation antitumor platinum complexes, [2,2-bis (aminomethyl)-1,3-propanediol-N,N']-[1,1-cyclobutanedicarboxylato (2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylato(2-)-O,O'] [tetrahydro-4H-pyran-4,4-dimethanamine-N,N']platinum(II).

The synthesis, stability, and antitumor activity of a series of water-soluble third generation platinum(II) complexes have been described. Among these complexes, [2,2-bis(aminomethyl)-1,3- propanediol-N,N'] [1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylate(2-)-O,O'](tetrahydro-4H-pyran-4,4- dimethanamine-N,N'-)platinum(II) have shown the greatest promise for further investigation and are currently under clinical evaluation.

Fast atom bombardment mass spectrometry of cisplatin analogs.

Cisplatin analogs of the type PtLACl2 and PtLALB are thermally unstable, non-volatile and highly insoluble. For these platinum coordination complexes, LA is a bidentate amine ligand and LB is a bidentate carboxylate ligand. Mass spectral data for structural elucidation of these compounds are absent in the literature because they are difficult to ionize. Nevertheless, a routine fast atom bombardment mass spectroscopic method has been developed utilizing the mixed solvent system of dimethyl sulfoxide:thioglycerol in a ratio of about 1:3 v/v. Using both positive and negative ionization modes, structurally significant ions were observed from representative molecules of the two named classes of compounds. [M-H]- ions were observed in both structural classes while [M + H]+ ions were observed only in the PtLALB class of compounds. Additional ions observed are rationalized in terms of the condensed-phase solution chemistry of the cisplatin analogs and the mixed solvent system when exposed to the fast atom beam. The two mechanisms causing ionization of the cisplatin analogs in the condensed phase appear to be: displacement of the ligands with dimethyl-sulfoxide and addition of chloride and the ionized solvents [dimentyl sulfoxide + H]+ and [thioglycerol - H]- to the cisplatin analogs. It is hypothesized that the addition reactions of the ionized solvents occur because of the differences in the basicity of the solvents and their reactivity in forming platinum(II)-sulfur bonds.