Michael Carland

Preparation of novel selenapenams and selenacephems by nucleophilic and radical chemistry involving benzyl selenides

2,2a-Dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (12), 5-selena-1-azabicyclo[4.2.0]oct-3-en-8-one (13), ethyl 1-aza-7-oxo-4-selenabicyclo[3.2.0]heptane-2-carboxylate (16), and benzoselenopenem (33) can be prepared in 39-85% yield through the intramolecular homolytic substitution of aryl, vinyl or alkyl radicals at the selenium atom in suitably-substituted 4-benzylseleno-beta-lactams, or through intramolecular nucleophilic substitution by the benzylseleno moiety in 4-halo-beta-lactam precursors. Application of this chemistry to the preparation of optically active selenium-containing analogues of beta-lactam antibiotics is also detailed.

Nucleophilic and radical chemistry of benzylselenides: preparation of novel selenocephems and selenopenams

Abstract Selenocephems ( 14 and 15 ) and selenopenams ( 18 , 20 , 24 and 25 ) can be prepared in 18–85% yields through the intramolecular homolytic substitution of aryl or alkyl radicals at the selenium atom in suitably-substituted 4-benzylseleno-β-lactams, or through intramolecular nucleophilic substitution by the benzylseleno moiety in 4-halo-β-lactam precursors.

Preparation of Novel Selenopenams by Intramolecular Homolytic Substitution

Photolyses of the thiohydroximate ester derivatives 13 and 21 of the 4- (benzyl-seleno)-2-azetidinoines 7 and 20, afford the 1-aza-7-oxo-4-selenabicyclo- [3.2.0]heptane ring systems 14 and 21 in good to moderate yield in processes that presumably involve intramolecular homolytic substitution at selenium with expulsion of benzyl radical. Extension of this methodology to the preparation of derivatives 24 of 12,2a-dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (22) is also described.

Substituted 9-aminoacridine-4-carboxamides tethered to platinum(II)diamine complexes: chemistry, cytotoxicity and DNA sequence selectivity.

Three platinum complexes in which substituted (7-OMe, 9-NH(2); 7-F, 9-NH(2); and 7-H, 9-NH(CH(2))(2)OH) 9-aminoacridine-4-carboxamides were tethered to a platinum(II)diamine moiety were synthesised and characterised at the chemical and biological level. These variants showed a decrease in cytotoxicity, as measured by IC(50) values in HeLa cells, when compared with the parent 7-H, 9-NH(2) compound. The 7-F and 9-NH(CH(2))(2)OH substituents gave rise to a small decrease in cytotoxicity, and the 7-OMe substituent resulted in a larger decrease in cytotoxicity. Their binding to purified pUC19 plasmid DNA was investigated and it was found that the addition of 7-F, 9-NH(CH(2))(2)OH and especially the 7-OMe substituents, resulted in reduced DNA binding. This correlated well with the IC(50) cytotoxicity values. However, the DNA sequence selectivity was unaffected by the addition of these moieties.

The DNA sequence selectivity of maltolato-containing cisplatin analogues in purified plasmid DNA and in intact human cells

Cisplatin analogues with an attached DNA binding moiety have a higher affinity for DNA, but often suffer from poor aqueous solubility. In this study we examined the DNA sequence specificity of more soluble cisplatin analogues containing the maltolato leaving group in both purified DNA and in intact human cells. In both environments the DNA sequence specificity of these analogues was very similar to cisplatin. However, in purified DNA a higher concentration of the two maltolato-containing analogues was needed to achieve a similar level of DNA damage as cisplatin. This difference in reactivity was not observed in intact cells as the two maltolato-containing complexes were capable of producing a similar level of damage as cisplatin at comparable concentrations. This was consistent with the IC(50) values obtained for both cisplatin and the maltolato compounds which were also similar. This study indicated that maltolato can be utilised as the leaving group to increase the aqueous solubility of cisplatin analogues without reducing their biological activity.

Hydrogen-bonded networks from novel platinum(II) dimers

The structures of the complexes: cis-dichloro[(2-(phenylselanyl)ethanamine]platinum(II) (1) and cis-dichloro[(2-(benzylyselanyl)ethanamine]platinum(II) (2) are reported. Self-complementary N–H⋯Cl interactions result in the generation of dimers. Through this dimerization the Pt centres are brought within 3.4905(5) A in the case of 1 and 3.6142(6) A in the case of 2. When each of the dimers is viewed along the Pt–Pt vector the Pt to donor atom bonds are eclipsed. Through further N–H⋯Cl interactions, 1 forms a chain while 2 forms a sheet.

Ethyl 2-(2-Ethoxy-2-oxoethylidene)-1,3-diselenole-4-carboxylate—an Example of Unconventional Bonding in Organic Selenides

Reaction of ethyl propiolate with lithium hexamethyldisilazide in tetrahydrofuran followed by the addition of elemental selenium provides ethyl 2-(2-ethoxy-2-oxoethylidene)-1,3-diselenole-4-carboxylate in 75p yield and as a mixture of geometrical isomers 2, 3. X-Ray crystallographic studies, as well as density functional calculations reveal close oxygen–selenium contacts that are the result of unconventional bonding interactions.