Synthesis and structure-activity relationship study of potent cytotoxic analogues of the marine alkaloid lamellarin D

Journal of Medicinal Chemistry

Volumn 49, Issue 11, 2006, Pages 3257-3268

  Pla, Daniel ^a   Marchal, Antonio ^a,e   Olsen, Christian A ^a,f   Francesch, Andres ^b   Cuevas, Carmen ^b   Albericio, Fernando ^a,c   Alvarez, Mercedes ^a,d  

^a UNIVERSITY OF BARCELONA   (Spain)

^b PHARMAMAR S A   (Spain)

^c Department of Organic Chemistry ^*  (Spain)

^d Faculty of Pharmacy   (Spain)

^e UNIVERSITY OF JAÉN   (Spain)

^f UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

ALKALOID; DNA TOPOISOMERASE INHIBITOR; LAMELLARIN D; METHYL 2 (2,4 DIHYDROXY 5 METHOXYPHENYL) 8 HYDROXY 1 (4 HYDROXY 3 METHOXYPHENYL) 9 METHOXYPYRROLO[2,1 A]ISOQUINOLINE 3 CARBOXYLIC ACID; METHYL 5,6 DIHYDROPYRROLO[2,1 A]ISOQUINOLINE 3 CARBOXYLIC ACID; UNCLASSIFIED DRUG;

ARTICLE; BREAST CANCER; CANCER CELL CULTURE; CARBON NUCLEAR MAGNETIC RESONANCE; COLON CARCINOMA; DRUG CYTOTOXICITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; LUNG CANCER; MARINE ENVIRONMENT; MOLECULAR DYNAMICS; MOLLUSC; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; COUMARINS; DNA TOPOISOMERASES, TYPE I; DRUG SCREENING ASSAYS, ANTITUMOR; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; ISOQUINOLINES; MODELS, MOLECULAR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33744796250     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0602458     Document Type: Article

References (47)

1. Dobson, C. M. Chemical Space and Biology. Nature 2004, 432, 824-828.
2. Breinbauer, R.; Vetter, I. R.; Waldmann, H. From Protein Domains to Drug Candidates-Natural Products as Guiding Principles in the Design and Synthesis of Compound Libraries. Angew. Chem., Int. Ed. 2002, 41, 2878-2890.
3. Balamurugan, R.; Dekker, F. J.; Waldmann, H. Design of Compound Libraries Based on Natural Product Scaffolds and Protein Structure Similarity Clustering (PSSC). Mol. Biosyst. 2005. 1, 36-45.
4. Newman, D. J.; Cragg, G. M.; Snader, K. M. Natural Products as Sources of New Drugs over the Period 1981-2002. J. Nat. Prod. 2003, 66, 1022-1037.
5. Clardy, J.; Walsh, C. Lessons from Natural Molecules. Nature 2004, 432, 829-837.
6. Jaroszewski, J. W. Hyphenated NMR Methods in Natural Products Research, Part 1: Direct Hyphenation. Planta Med. 2005, 71, 691-700.
7. Jaroszewski, J. W. Hyphenated NMR Methods in Natural Products Research, Part 2: HPLC-SPE-NMR and Other New Trends in NMR Hyphenation. Planta Med. 2005, 71, 795-802.
8. Rouhi, A. M. Rediscovering Natural Products. Chem. Eng. News. 2003, 81, 77-91.
9. König, G. M.; Kehraus, S.; Seibert, S. F.; Abdel-Lateff, A.; Müller, D. Natural Products from Marine Organisms and Their Associated Microbes. ChemBioChem 2006, 7, 229-238.
10. Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van Duyne, G. D.; Clardy, J. Metabolites of the Marine Prosobranch Mollusc Lamellaria sp. J. Am. Chem. Soc. 1985, 107, 5492-5495.
11. Cironi, P.; Albericio, F.; Álvarez, M. Lamellarins: Isolation, Activity and Synthesis. In Progress in Heterocyclic Chemistry, Gribble, G. W., Joule, J. A., Eds.; Pergamon: Oxford, U.K., 2004; Vol. 16, pp 1-26.
12. Bailly, C. Lamellarins, from A to Z: A Family of Anticancer Marine Pyrrole Alkaloids. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363-378.
13. Facompré, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Pérez, C.; Manzanares, I.; Cuevas, C.; Bailly, C. Lamellarin D: A Novel Inhibitor of Topoisomerase I. Cancer Res. 2003, 63, 7392-7399.
14. Vanhuyse, M.; Kluza, J.; Tardy, C.; Otero, G.; Cuevas, C.; Bailly, C.; Lansiaux, A. Lamellarin D: A Novel Pro-Apoptotic Agent from Marine Origin Insensitive to P-Glycoprotein-Mediated Drug Efflux. Cancer Lett. 2005, 227, 165-175.
15. Staker, B. L.; Hjerrild, K.; Feese, M. D.; Behnke, C. A.; Burgin, A. B., Jr.; Stewart, L. The Mechanism of Topoisomerase I Poisoning by a Camptothecin Analog. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15387-15392.
16. Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly, C.; Gago, F. Molecular Determinants of Topoisomerase I Poisoning by Lamellarins: Comparison with Camptothecin and Structure-Activity Relationships. J. Med. Chem. 2005, 48, 3796-3807.
17. Ishibashi, F.; Tanabe, S.; Oda, T.; Iwao M. Synthesis and Structure-Activity Relationship Study of Lamellarin Derivatives. J. Nat. Prod. 2002, 65, 500-504.
18. Tardy, C.; Facompré, M.; Laine, W.; Baldeyrou, B.; García-Gravalos, D.; Francesch, A.; Mateo, C.; Pastor, A.; Jiménez, J. A.; Manzanares, I.; Cuevas C.; Bailly, C. Topoisomerase 1-Mediated DNA Cleavage as a Guide to the Development of Antitumor Agents Derived from the Marine Alkaloid Lamellarin D: Triester Derivatives Incorporating Amino Acid Residues. Bioorg. Med. Chem. 2004, 12, 1697-1712.
19. Olsen, C. A.; Parera, N.; Albericio, F.; Alvarez, M. 5,6- Dihydropyrrolo[2,1-α]isoquinolines as Scaffolds for Synthesis of Lamellarin Analogues. Tetrahedron Lett. 2005, 46, 2041-2044.
20. For clarity, in this article, the numbering of the lamellarins and the scaffold is as in ref 15.
21. Heim, A.; Terpin, A.; Steglich, W. Biomimetic Synthesis of Lamellarin G Trimethyl Ether. Angew. Chem., Int. Ed. 1997, 36, 155-156.
22. Ishibashi, F.; Miyazaki, Y.; Iwao, M. Total Synthesis of Lamellarin D and H. The First Synthesis of Lamellarin-Class Marine Alkaloids. Tetrahedron 1997, 53, 5951-5962.
23. Banwell, M.; Flynn, B.; Hockless, D. Convergent Total Synthesis of Lamellarin K. Chem. Commun. 1997, 2259-2260.
24. Cironi, P.; Manzanares, I.; Albericio, F.; Álvarez, M. Solid-Phase Total Synthesis of Pentacyclic System Lamellarins U and L. Org. Lett. 2003, 5, 2959-2962.
25. Marfil, M.; Albericio, F.; Álvarez, M. Solid-Phase Synthesis of Lamellarins Q and O. Tetrahedron 2004, 60, 8659-8668.
26. Cironi, P.; Cuevas, C.; Albericio, F.; Álvarez, M. Gaining Diversity in Solid-Phase Synthesis by Modulation of Cleavage Conditions from Hydroxymethyl-Based Supports. Application to Lamellarins. Tetrahedron 2004, 60, 8669-8675.
27. Pla, D.; Marchai, A.; Olsen, C. A.; Albericio, F.; Álvarez, M. Modular Total Synthesis of Lamellarin D. J. Org. Chem. 2005, 70, 8231-8234.
28. Fujikawa, N.; Ohta, T.; Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Total Synthesis of Lamellarins D, L, and N. Tetrahedron 2006, 62, 594-604.
29. An advantage of the protection was the increase in solubility of the compounds throughout the synthetic process as well as the prevention of undesired processes.
30. Compound 4d was not used as a building block. This entry is in the Table to introduce the substituents of compounds 6d, 8d, and 1Od.
31. (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K. Fraange. New Diphosphine Ligands Based on Heterocyclic Aromatics Inducing Very High Regioselectivity in Rhodium-Catalyzed Hydroformylation: Effect of the Bite Angle. Organometallics 1995, 14, 3081-3089.
32. (b) Wolfe, J. P.; Singer, R. A.; Bryant, H. Y.; Buchwald, S. L. Highly Active Palladium Catalysts for Suzuki Coupling Reactions. J. Am. Chem. Soc. 1999, 121, 9550-9561.
33. To obtain 2, 3, and 8, the protection of the phenolic groups is crucial to avoid byproducts during bromination.
34. Regioselectivity on the bromination of 6 to give 8 was easily checked by the absence of the singlet at 6.7 ppm, characteristic of H-2.
35. A lower reaction time than that for the less electron-rich analogues or the lower reaction temperature did not improve the results.
36. In a previous study on the preparation of Lam-D (ref 27), an excess of 6 equiv of boronate were used; however, the reduction of that amount to 3 equiv did not produce a significant change in the reaction yield.
37. 1H-NMR analyses evidenced the presence of an equimolecular amount of 1-aryl- and 2-aryl-bromides and. therefore, the absence of regioselectivity.
38. Sotomayor, N.; Domínguez, E.; Lete. E. Oxidation Reactions of 2′-Functionalized 3-Aryltetrahydro and 3.4-Dihydroisoquinolines. Tetrahedron 1995, 57, 12721-12730.
39. Bermejo, A.; Andreu, I.; Suvire, F.; Leonce, S.; Caignard, D. H.; Renard, P.; Pierre, A.; Enriz, R. D.; Cortes, D.; Cabedo, N. Syntheses and Antitumor Targeting Gl Phase of the Cell Cycle of Benzoyldihydroisoquinolines and Related 1-Substituted Isoquinolines. J. Med. Chem. 2002, 45, 5058-5068.
40. It was not possible to oxidize scaffold 1, 61, and 71 using this procedure.
41. Both double doublets were assigned by gHSQC to C5"-H. See the gHSQC of 12f in the Supporting Information.
42. Semiempirical method PM3 was used for the energy minimization of each rotamer.
43. Mata, E. G. β-Lactams on Solid Support: Mild and Efficient Removal of Penicillin Derivatives from Merrifield Resin using Aluminum Chloride. Tetrahedron Lett. 1997, 38, 6335-6338.
44. 3 in 16a and 17a.
45. 8) to give OH.
46. (a) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Waren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. New Colorimetric Cytotoxicity Assay for Anticancer Drug Screening. J. Natl. Cancer Inst. 1990, 82, 1107-1112.
47. (b) Faircloth, G. T.; Stewart, D.; Clement, J. J. A Simple Screening Procedure for the Quantitative Measurement of Cytotoxicity Assay. J. Tissue Cult. Methods 1988, 11, 201-205.