We have developed a method to image tumor-associated lysosomal protease activity in a xenograft mouse model in vivo using autoquenched near-infrared fluorescence (NIRF) probes. NIRF probes were bound to a long circulating graft copolymer consisting of poly-L-lysine and methoxypolyethylene glycol succinate. Following intravenous injection, the NIRF probe carrier accumulated in solid tumors due to its long circulation time and leakage through tumor neovasculature. Intratumoral NIRF signal was generated by lysosomal proteases in tumor cells that cleave the macromolecule, thereby releasing previously quenched fluorochrome. In vivo imaging showed a 12-fold increase in NIRF signal, allowing the detection of tumors with submillimeter-sized diameters. This strategy can be used to detect such early stage tumors in vivo and to probe for specific enzyme activity.

In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.

Design and therapeutic application of matrix metalloproteinase inhibitors.

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

https://www.hemonc.theclinics.com/article/S0889-8588(02)00044-8/pdf

Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy

https://helda.helsinki.fi/bitstream/handle/10138/22049/gelatina.pdf?sequence=1

Gelatinase-mediated migration and invasion of cancer cells.

Our previous studies have clearly shown that the angiogenic enzymes, matrix metalloproteinase (MMP) -2/9, are directly involved in human hepatic tumorigenesis and metastasis and suggest that the MMP-2/9 inhibitors, which have dual inhibitory activities on enzyme activity and transcription, represent the best candidates for achieving tumor regression. Many anti-cancer drugs have strong cellular cytotoxicity and side effects, indicating that strong anti-cancer drugs that have no or minimal cytotoxicity and side effects need to be developed. The specific aim of the present study was to develop powerful anti-cancer drugs with specific tumor regression and anti-metastatic potential having the dual inhibitory activities of specific MMP-2 and -9 enzyme activities and gene transcription at the molecular level. Caffeic acid (CA), a strong and selective MMP-9 activity and transcription inhibitor, was isolated from the plant Euonymus alatus and its derivative, caffeic acid phenethyl ester (CAPE), was synthesized. CA...

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.04-2126com

Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism

Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Total synthesis of (-)-PA-48153C, a novel immunosuppressive 2-pyranone derivative

Alkylation enantioselective des dianions derives des monoesters chiraux d'acides maloniques monosubstitues avec des halogenures d'alkyles

Enantioselective construction of a quaternary asymmetric carbon center: a versatile synthesis of .alpha.-alkyl .alpha.-amino acids

Both enantiomers of the menthyl half-esters (10) and (23) of ethylmalonic acid were converted into(+)-(4S,5R)-4-(2-benzyloxyethyl)-5-ethyl-3,4,5,6-tetrahydro-2-pyrone (18). A mixture of the trans-(18) and cis-lactones (19) in a ratio of ca. 4 : 1 was prepared by way of radical cyclisation of the (E)-α,β-unsaturated esters (16), while the former (18) was synthesised with high stereoselection by the cyclisation of the (Z)-esters (26). The lactone (18) was enantioselectively transformed into (–)-protoemetimol (5) and (–)-protoemetine (4), correlated to (–)-emetine (1) and (–)-tubulosine (3).

Asymmetric total synthesis of(–)-protoemetinol,(–)-protoemetine,(–)-emetine, and (–)-tubulosine by highly stereocontrolled radical cyclisations

5beta-Methoxy (20), 14-methyl (24), 14,14-dibromo-15-nor (25), 8-O-acyl (26-45), 8-O-alkyl (46), 8-O-alkoxycarbonyl (47, 48), and 8-O-carbamoyl (49) derivatives of PA-48153C, a novel immunosuppressant isolated from fermentation products of Streptomyces prunicolor PA-48153, were prepared. These compounds were found to retain the inhibitory activity on the responses of both T and B cells to mitogens. Among them, the C-8 hexanoate 28 showed potent suppressive effects on mitogen responses with less cytotoxicity to EL4 cells and was selected for in vivo evaluation.

Ken Yasui

Papers

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Total synthesis of (-)-PA-48153C, a novel immunosuppressive 2-pyranone derivative

Enantioselective construction of a quaternary asymmetric carbon center: a versatile synthesis of .alpha.-alkyl .alpha.-amino acids

Asymmetric total synthesis of(–)-protoemetinol,(–)-protoemetine,(–)-emetine, and (–)-tubulosine by highly stereocontrolled radical cyclisations

Chemical Modification of PA-48153C, a Novel Immunosuppressant Isolated from Streptomyces prunicolor PA-48153.