Ettore Perrone

Matrix metalloproteinase inhibitors

The matrix metalloproteinases (MMPs) are a family of at least fifteen secreted and membrane-bound zinc-endopeptidases. Collectively, these enzymes can degrade all of the components of the extracellular matrix, including fibrallar and non-fibrallar collagens, fibronectin, laminin and basement membrane glycoproteins. MMPs are thought to be essential for the diverse invasive processes of angiogenesis and tumor metastasis. Numerous studies have shown that there is a close association between expression of various members of the MMP family by tumors and their proliferative and invasive behavior and metastatic potential. In some of human cancers a positive correlation has also been demonstrated between the intensity of new blood vessel growth (angiogenesis) and the likelihood of developing metastases. Thus, control of MMP activity in these two different contexts has generated considerable interest as a possible therapeutic target.The tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring proteins that specifically inhibit matrix metalloproteinases, thus maintaining balance between matrix destruction and formation. An imbalance between MMPs and the associated TIMPs may play a significant role in the invasive phenotype of malignant tumors. TIMP-1 has been shown to inhibit tumor-induced angiogenesis in experimental systems. These findings raised the possibility of using an agent that affects expression or activity of MMPs as an anti-cancer therapy. TIMPs are probably not suitable for pharmacologic applications due to their short half-life in vivo.Batimastat (BB-94) and marimastat (BB-2516) are synthetic, low-molecular weight MMP inhibitors. They have a collagen-mimicking hydroxamate structure, which facilitates chelation of the zinc ion in the active site of the MMPs. These compounds inhibit MMPs potently and specifically. Batimastat was the first synthetic MMP inhibitor studied in humans with advanced malignancies, but its usefulness has been limited by extremely poor water solubility, which required intraperitoneal administration of the drug as a detergent emulsion. Marimastat belongs to a second generation of MMP inhibitors. In contrast to batimastat, marimastat is orally available. Both of these agents are currently in Phase I/II trials in US, Europe and Canada.Some other new agents, currently in clinical trials, have been shown to inhibit MMP production. Bryostatins, naturally occurring macrocyclic lactones, have both in vitro and in vivo activity in numerous murine and human tumors. In culture, bryostatin-1 has been shown to induce differentiation and halt the growth of several malignant cell lines. While the exact mechanism responsible for anti-tumor activity is unclear, an initial event in the action of bryostatin-1 is activation of protein kinase C (PKC), followed by its down regulation. Bryostatin-1 does not directly affect the activity of MMPs, but it can inhibit the production of MMP-1, 3, 9, 10 and 11 by inhibiting PKC. TIMP-1 levels could also be modulated by bryostatin-1, as it is encoded by a PKC responsive gene.

The carbonyl-carbonyl coupling route to penems : a stepwise analysis

Abstract Preparation and reactivity of novel azetidinyl(phosphoranylidene)acetates implicated in penem synthesis is discussed

2-Selenacephems and 1-dethia-1-selenapenems

Abstract The first selena nuclear analogues of β-lactam antibiotics have been synthesized and compared with their sulphur counterparts.

Synthesis and evaluation of new elastase inhibitors. I. 1,1-Dioxocephem-4-thiolesters

Several 7α-chloro and 7α-methoxy cephalosporin thiolester sulphones variously substituted at the C-3′ position were synthesized from 7-amino-3-deacetoxycephalosporanic acid (7-ADCA). The compounds are time-dependent inhibitors of human leukocyte elastase (HLE) with effective Ki ranging from micro- to nanomolar values, and second order rate constant reaching 106 M−1s−1; they also inhibit porcine pancreatic elastase with similar, though not identical efficiency. Compared to the corresponding cephem esters, the thiolesters of the 7-Cl series inhibit HLE up to 10 times as fast. Complete enzyme inactivation is achieved when a leaving group at C-3′ (OAc or S-Het) is present, at the expense however of stability towards hydrolytic β-lactam cleavage. In the 7-OMe series the thiolester compounds are far more stable and retain good efficiency for irreversible enzyme inhibition, superior to that displayed by the corresponding ester compounds. Three representative compounds (including one ester and two thiolesters) are shown to be effective inhibitors of HLE in the presence of insoluble elastin.

2-(Heteroatom-substituted)methyl penems. IV, Oxygen derivatives

The synthesis of 2-CH 2 X3 penems wherein X is an oxygen atom of an acyloxy, N-substituted carbamoyloxy, alkoxy or aryloxy residue is described, with emphasis to procedures which exploit a common 2-hydroxymethylpenem precursor. Correlations are attempted between chemical structure of the X moiety and antibacterial activity of obtained compounds.

On the Preparation of 4-Hydroxymethyl-5-Methyl-1,3-Dioxol-2-One

Abstract A practical and efficient conversion of 4-bromomethyl-5-methyl-1, 3-dioxol-2-one 1 into the corresponding carbinol 2, a useful building block for the preparation of prodrugs, is reported.

Synthesis of novel cephem-4-ketones. A new series of human leukocyte elastase inhibitors

Alkylation of cephem-4-carbonyl chlorides at the sulphide or sulphone oxidation level with Grignard reagents, stannanes and cuprates is described. Radical or ionic bromination of the 3-methylcephem-4-ketone 8, followed by displacement with heterocyclic thiols, provides an entry to 3′- and 2-thiosubstituted derivatives, which are new potent inhibitors of HLE. Alkylation of cephem-4-carbonyl chlorides with Grignard reagents, stannanes or cuprates, prior or after oxidation, gave 3a≈f(X Cl; R But, Et, Ph.Bz.H; R′OAc). Similarly, 8 (X OMe, R But, R′ H) was prepared and converted to 13a≈c (R′ S-Het) and 14a≈c via radical and ionic bromination, respectively. The new cephem-4-ketones are potent inhibitors of human leukocyte elastase.

Cephem sulfones as inactivators of human leukocyte elastase. II. Keto-enol tautomerish in cephem-4-ketones.

Abstract Keto-enol tautomerism has been investigated in cephem-4-ketones, a new class of human leukocyte elastase inhibitors. Efficient enzyme inhibition was found compatible with ionization of the compounds as enolates, which confers solubility and hydrolytic stability at physiological pH.

Desulphurative approaches to penem antibiotics. III. Synthesis and desulphurisation of 3-methyl-2-thiacephem-4-carboxylates

Abstract Displacement of leaving groups from a number of 2-oxo-azetidin-4-ylthio derivatives with sulphide or hydrosulphide salts conveniently affords 2-thiacephem, whose desulphurisation gives penems.

Synthesis of Penems

The synthesis of penems has been the object of intensive research in the last decade. Stereoselective synthesis of azetidinones, chemoselective cleavage of the thiazolidine ring of penicillins, hydroxy- ethylation at the lactam α-carbon, and penem annulation reactions are the important issues addressed in this work. By confronting possibilities with achievements, a comprehensive but readable survey of this chapter of antibiotic chemistry is attempted.