Arun Ghosh

Iron transport-mediated drug delivery using mixed-ligand siderophore-β-lactam conjugates

BACKGROUND Assimilation of iron is essential for microbial growth. Most microbes synthesize and excrete low molecular weight iron chelators called siderophores to sequester and deliver iron by active transport processes. Specific outer membrane proteins recognize, bind and initiate transport of species-selective ferric siderophore complexes. Organisms most often have specific receptors for multiple types of siderophores, presumably to ensure adequate acquisition of the iron that is essential for their growth. Conjugation of drugs to synthetic hydroxamate or catechol siderophore components can facilitate active iron-transport-mediated drug delivery. While resistance to the siderophore-drug conjugates frequently occurs by selection of mutants deficient in the corresponding siderophore-selective outer membrane receptor, the mutants are less able to survive under iron-deficient conditions and in vivo. We anticipated that synthesis of mixed ligand siderophore-drug conjugates would allow active drug delivery by multiple iron receptor recognition and transport processes, further reducing the likelihood that resistant mutants would be viable. RESULTS Mixed ligand siderophore-drug conjugates were synthesized by combining hydroxamate and catechol components in a single compound that could chelate iron, and that also contained a covalent linkage to carbacephalosporins, as representative drugs. The new conjugates appear to be assimilated by multiple active iron-transport processes both in wild type microbes and in selected mutants that are deficient in some outer membrane iron-transport receptors. CONCLUSIONS The concept of active iron-transport-mediated drug delivery can now be extended to drug conjugates that can enter the cell through multiple outer membrane receptors. Mutants that are resistant to such conjugates should be severely impaired in iron uptake, and therefore particularly prone to iron starvation.

SELECTIVE GROWTH PROMOTION AND GROWTH INHIBITION OF GRAM-NEGATIVE AND GRAM-POSITIVE BACTERIA BY SYNTHETIC SIDEROPHORE-BETA -LACTAM CONJUGATES

Conjugates of a carbacephalosporin with hydroxamate, spermexatol, N,N-bis(2,3-dihydroxybenzoyl)-L-lysine, mixed catecholate/hydroxamate and cyanuric acid-based siderophores were investigated for their potential to promote growth of siderophore indicator strains of Gram-negative and Gram-positive bacteria under iron depleted conditions, for their antibacterial activity and for their ability to use iron transport path-ways to penetrate the Gram-negative bacterial outer membrane. The selective growth promotion of enter-obacterial and pseudomonas strains by hydroxamate, spermexatol and mixed catecholate-hydroxamate siderophore-based conjugates bearing a L- or D-amino acid spacer was correlated with TonB dependent uptake routes. The preferred outer membrane siderophore receptor used in Escherichia coli was found to be Fiu, followed by Cir. Antagonistic effects of siderophores administered with the conjugates to determine antibacterial activity confirmed the active transport of conjugates via siderophore receptors. All of the conjugates were still able to diffuse through the porin proteins OmpC and OmpF. Nevertheless, strong inhibition of E. coli and Pseudomones aeruginosa outer membrane mutants DC2 and K799/61 compared to the parent strains indicated inefficient penetrability of all types of conjugates tested. Mycobacterium smegmatis SG 987 was able to use all of the siderophore-cephalosporin conjugates as growth promotors. Consequently there was no growth inhibition of this strain.

Efficient functionalization of acylnitroso cycloadducts: Application to the syntheses of carbocyclic nucleoside precursors

Abstract 1,4- cis -disubstituted cyclopentene precursors of carbocyclic nucleotides were readily prepared utilizing acylnitroso hetero Diels-Alder reactions and Pd(0)-catalyzed alkylation reactions as the key steps. The chemistry was explored in both racemic and asymmetric fashion. The hydroxymethyl components of the carbocyclic nucleoside precursors were obtained from nitromethyl groups under oxidative Nef conditions and may be further elaborated into a variety of compounds of potential biological interest.

Stereocontrolled syntheses of some conformationally restricted analogs of serotonin

Abstract Syntheses of serotonin analogs 2 and 3 are described including a case of retention in the Mitsunobu reaction. An unusual stereoselectivity in a reductive amination sequence is also described. Dopamine and serotonin activity of the eight analogs has been determined.

SYNTHESIS OF NOVEL HYDANTOIN ANALOGS OF 5'-NOR CARBOCYCLIC NUCLEOSIDES : VERSATILITY OF A CHIRAL ACYLNITROSO CYCLOADDITION

Abstract An asymmetric hetero-Diels-Alder reaction involving an amino acid-derived acylnitroso dienophile was utilized to synthesize novel hydantoin analogs ( 12 ) of carbocyclic nucleosides. The hydantoins were formed during an attempted protection of an amide nitrogen.

Mn(III) promoted N-O bond reduction of N-hydroxy-2-azetidinones

Abstract Treatment of various N-hydroxy-2-azetidinones with Mn(III) acetate unexpectedly afforded the corresponding reduced N-unsubstituted-2-azetidinones in the presence of hydrogen donor solvents.