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Objective Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. Methods Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)–induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. Results A number of non–hydroxamic acid–containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1α– and oncostatin M–induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean ± SEM damage score 1.3 ± 0.3, versus 2.2 ± 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. Conclusion The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.

This review is a survey of two approaches for a selective anticancer therapy that are based on a specific cleavage of specially designed non-toxic prodrugs with the liberation of a cytotoxic compound either by antibody-enzyme conjugates targeted to tumor-associated antigens or by acid-catalyzed hydrolysis of the prodrugs due to the increased concentration of hydronium ions in malignant tissue under hyperglycemic conditions. Herein, the design, synthesis and the biological testing of prodrugs are described.

Novel seco-analogs of CC-1065 1 were synthesized from comercially available nitroaniline by reduction, bromination, bisulfonation and bisallylation followed by reaction with tert-butyllithium, zirconocene and iodine. The obtained quinoline 6 was then transformed into 17 and 18, which, upon treatment with Pd0, led to 21 and 22, respectively. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Summary Background and Aim: In recent years, much research interest has been rightfully directed towards modelling human disease. The increasing demand of laboratory animals has led to a major impetus in small animal imaging. We evaluated the feasibility of using multislice spiral CT (MSCT) technology in a severe combined immunodeficiency (SCID) mouse model for non-small cell lung cancer. Materials and Methods: Mice (n = 14) were implanted orthotopically with the human non-small cell lung adenocarcinoma cell line A 549. Mice were scanned with MSCT and sacrificed 7 days (n = 3), 14 days (n = 3), and 21 days (n = 5) after tumor cell implantation, respectively. Histopathology was performed. Tumor size as revealed by imaging and pathology was correlated. A group of animals (n = 3) received anti-cancer treatment with seco-CBI-Q-galatoside. Those mice were scanned with MSCT 21 days after tumor implantation and sacrificed, and histopathologic work-up was performed. Results: A total of 14 mice with 14 macroscopically visible and 5 microscopically appreciable adenocarcinomas of the lung were examined. All macroscopically visible tumors were readily depicted with MSCT except from 2 lesions of 1 mm in diameter. MSCT accurately displayed the different tumor sizes in treated vs. non-treated animals. Discussion: MSCT proved to be a valuable tool for imaging of a murine lung cancer model. This evidences a potential use of this technology in small animal lung cancer imaging.

A short and efficient synthesis of seco-duocarmycin SA (3), a highly potent cytostatic agent and direct precursor of the natural product duocarmycin SA (1), has been achieved. Starting from commercially available 2-methoxy-4-nitroaniline (4) the synthetic protocol contains a Fischer indole synthesis to introduce the heterocyclic scaffold and a radical 5-exo-trig cyclization to furnish the (chloromethyl)indoline ring system as key reactions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

This paper describes novel seco-analogues 25−27 of the cytotoxic antibiotic CC-1065 (1) and their prodrugs 5, 6a, and 6b, for antibody-directed enzyme prodrug therapy (ADEPT). The partially hydrogenated seco-CCI-analogue 7 and the corresponding methyl-CCI analogues 8a and 8b were synthesized by alkylation of 9 with 15 and 16, respectively, followed by radical cyclization and deprotection. Treatment of 7, 8a, and 8b with the galactose trichloroacetimidate 21 and the bisindolyl-carboxylic acid 20 in the presence of EDC followed by solvolysis gave the desired prodrugs 5, 6a, and 6b, respectively. Compounds 25−27 were prepared by treatment of 7, 8a, and 8b with 20 after deprotection. In vitro tests showed a strong cytotoxicity for 25 and a fairly low toxicities for 26 and 27. However, the selectivity of the prodrugs 5, 6a, and 6b was not sufficient for ADEPT. Interestingly, 8a and 8b did not undergo Winstein cyclization to produce the spirocyclopropylcyclohexadienone moiety. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Antibody-directed enzyme prodrug therapy (ADEPT) is a recent development for a selective treatment of cancer, based on site-directed formation at the surface of malignant cells of cytotoxic compounds from non-toxic prodrugs with a conjugate of an appropriate enzyme and a monoclonal antibody which binds to tumour-associated antigens. New potent prodrugs of analogues of the antibiotic CC-1065 have been developed. These show a remarkable selectivity with a Q(IC50) value of up to more than 3000. Moreover, the formed drug has a high potency with an IC50 of 30 pM.

A short and efficient synthesis of seco-duocarmycin SA (3), a highly potent cytostatic agent and direct precursor of the natural product duocarmycin SA (1), has been achieved. Starting from commercially available 2-methoxy-4-nitroaniline (4) the synthetic protocol contains a Fischer indole synthesis to introduce the heterocyclic scaffold and a radical 5-exo-trig cyclization to furnish the (chloromethyl)indoline ring system as key reactions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Antibody-directed enzyme prodrug therapy (ADEPT) is a recent development for a selective treatment of cancer, based on site-directed formation at the surface of malignant cells of cytotoxic compounds from non-toxic prodrugs with a conjugate of an appropriate enzyme and a monoclonal antibody which binds to tumour-associated antigens. New potent prodrugs of analogues of the antibiotic CC-1065 have been developed. These show a remarkable selectivity with a Q(IC50) value of up to more than 3000. Moreover, the formed drug has a high potency with an IC50 of 30 pM.