1-Imidazolylcarbonyloxy-substituted Tetrahydroquinolines and Pyridines: Synthesis and Evaluation of P450 TxA2 Inhibition

Hartmann, Rolf W.; Frotscher, Martin

doi:10.1002/(sici)1521-4184(199910)332:10<358::aid-ardp358>3.0.co;2-d

Cited by 14 publications

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“…In our group the rational design of P450 TxA 2 inhibitors resulted in a wide variety of substrate mimetics, that inhibited TxA 2 formation in thrombocytes (Ledergerber et al 1997;Hartmann and Frotscher 1999;Jacobs et al 2000). Several compounds with low IC 50 values were tested for their ability to inhibit the adhesion of P450 TxA 2 -positive tumor cells (MDA MB 231, DU145, and U937) to the basement membrane.…”

Section: Introductionmentioning

confidence: 99%

No effect of thromboxane A2 on the attachment of tumor cell lines MDA MB 231, DU145, and U937 to the basement membrane in an in-vitro model.

Kleber

Jose

2001

J Cancer Res Clin Oncol

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Purpose: A broad body of evidence indicates the involvement of P450 TxA 2 (thromboxane A 2 synthetase) in tumor metastasis formation. A distinct function of the enzyme in this multistep process, however, is still unknown. Therefore the eect of TxA 2 (thromboxane A 2 ) on tumor cell adhesion to the basement membrane, a key event in metastasis formation, was investigated. Methods: A wide variety of compounds designed in our work group and identi®ed as P450 TxA 2 inhibitors were applied to several P450 TxA 2 -positive tumor cell lines to test their in¯uence on tumor cell adhesion. For this purpose an in-vitro basement membrane adhesion model with the matrix gel preparation Matrigel was used. Results: Most of the P450 TxA 2 inhibitors tested had no eect on cell adhesion. Although two compounds signi®cantly reduced tumor cell adhesion in a concentration-dependent manner, this was not related to P450 TxA 2 inhibition. Conclusion: These data indicate that TxA 2 might not be involved in the attachment of tumor cell lines to the basement membrane.Keywords P450 TxA 2 á Inhibitors á Metastasis á Tumor cell adhesion á Basement membrane Materials and methodsCell lines U937 (promonocytic human cell line) and DU145 (epithelial-like, adherent cell line, established from a prostate adenocarcinoma metastasis) were obtained from the DSMZ (Braunschweig, Germany).

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Section: Introductionmentioning

confidence: 99%

No effect of thromboxane A2 on the attachment of tumor cell lines MDA MB 231, DU145, and U937 to the basement membrane in an in-vitro model.

Kleber

Jose

2001

J Cancer Res Clin Oncol

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Discovery of Inhibitors of MCF‐7 Tumor Cell Adhesion to Endothelial Cells and Investigation on their Mode of Action

Bild

Jose

Hartmann

2004

Archiv der Pharmazie

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Metastasis, the main reason for high mortality of cancer, is a multistep process. One important step in this process is the adhesion of tumor cells to vascular endothelium at sites distant from primary tumors during hematogenous dissemination. In order to investigate and quantify the adhesion of tumor cells to endothelial cells we developed an in vitro model using MCF-7 breast cancer cells and monolayers of human umbilical vein endothelial cells (HUVEC). The tumor cells were specifically labeled with a fluorescent dye for quantification; for increasing the amount of adherent cells, HUVEC monolayers were stimulated with phorbol ester before the addition of the tumor cells. Due to previous reports that products of several P450 enzymes contribute to the progression of certain kinds of cancer, inhibitors of CYP5 (thromboxane A(2) synthase), CYP17 (17alpha-hydroxylase-C17, 20-lyase), and CYP19 (aromatase) were tested in this in vitro model for their potency to reduce cancer cell adhesion. Within each series of P450 inhibitors, compounds with high inhibitory activity on tumor cell adhesion were identified. At an initial concentration of 100 microM, BW26, a potent inhibitor of CYP5, reduced tumor cell adhesion of MCF-7 to HUVECs to 15%, BW40 (CYP17) to 29%, and SU5a (CYP19) to 11% of the corresponding controls (no inhibitor). Reduction of tumor cell adhesion was shown to occur in a concentration-dependent manner. In addition to these inhibitors of CYP5, CYP17, and CYP19, liarozole, known to be a potent inhibitor of CYP26 (retinoic acid-4-hydroxylase) and ATRA (all-trans-retinoic acid) metabolism, was able to reduce tumor cell adhesion to 51% of the initial rate. Experiments elucidating the mode of action of these compounds revealed that inhibition of the mentioned CYP enzymes is not responsible for their ability to reduce tumor cell adhesion.

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Regioselective Partial Hydrogenation and Deuteration of Tetracyclic (Hetero)aromatic Systems Using a Simple Heterogeneous Catalyst

Kehoe,

Lowry,

Light

et al. 2024

Chemistry A European J

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The introduction of added ‘3‐dimensionality’ through late‐stage functionalization of extended (hetero)aromatic systems is a powerful synthetic approach. The abundance of starting materials and cross‐coupling methodologies to access the precursors allows for highly diverse products. Subsequent selective partial reduction can alter the core structure in a manner of interest to medicinal chemists. Herein, we describe the precise, partial reduction of multicyclic heteroaromatic systems using a simple heterogeneous catalyst. The approach can be extended to introduce deuterium (again at late‐stage). Excellent yields can be obtained using simple reaction conditions.

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1-Imidazolylcarbonyloxy-substituted Tetrahydroquinolines and Pyridines: Synthesis and Evaluation of P450 TxA2 Inhibition

Cited by 14 publications

References 10 publications

No effect of thromboxane A2 on the attachment of tumor cell lines MDA MB 231, DU145, and U937 to the basement membrane in an in-vitro model.

No effect of thromboxane A2 on the attachment of tumor cell lines MDA MB 231, DU145, and U937 to the basement membrane in an in-vitro model.

Discovery of Inhibitors of MCF‐7 Tumor Cell Adhesion to Endothelial Cells and Investigation on their Mode of Action

Regioselective Partial Hydrogenation and Deuteration of Tetracyclic (Hetero)aromatic Systems Using a Simple Heterogeneous Catalyst

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