New Ras CAAX mimetics: Design, synthesis, antiproliferative activity, and RAS prenylation inhibition

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 18, 2009, Pages 5500-5504

  Bolchi, Cristiano ^a   Pallavicini, Marco ^a   Fumagalli, Laura ^a   Ferri, Nicola ^a   Corsini, Alberto ^a   Rusconi, Chiara ^a   Valoti, Ermanno ^a  

^a UNIVERSITY OF MILAN   (Italy)

Author keywords

Antiproliferative agents; Antitumors; Peptidomimetic inhibitors; Prenylation inhibitors

Indexed keywords

2 AMINOMETHYLBENZODIOXANE; 2 HYDROXYMETHYLBENZODIOXANE; [2 (4 TOLYL) 4 (1,4 BENZODIOXAN 2 YLMETHOXY)BENZAMIDO] 4 METHYLTHIOBUTYRIC ACID METHYL ESTER; ANTINEOPLASTIC AGENT; CARBOXY TERMINAL TELOPEPTIDE; CYSTEINE; DIOXANE DERIVATIVE; GLYCINE; LEUCINE; METHIONINE; PEPTIDOMIMETIC AGENT; RAS PROTEIN; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG DESIGN; DRUG MECHANISM; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IC 50; PROTEIN PRENYLATION; STRUCTURE ACTIVITY RELATION;

AORTA; BIOMIMETICS; CELL PROLIFERATION; HUMANS; MYOCYTES, SMOOTH MUSCLE; PEPTIDES; PRENYLATION; RAS PROTEINS;

EID: 68949127105     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.065     Document Type: Article

References (67)

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15. 3) δ 8.49 (d, J = 2.2 Hz, 1H), 8.19 (dd, J = 8.8, 2.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H).
16. 3) δ 8.26 (dd, J = 8.4, 2.2 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.32-7.23 (m, 3H), 7.07 (dd, J = 7.6, 6.6 Hz 1H), 3.65 (s, 3H), 2.09 (s, 3H).
17. 3) δ 8.23 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 2.3, 2.2 Hz, 1H), 7.97 (d, J = 9.15 Hz, 1H), 7.4 (m, 1H), 7.28 (m, 1H), 7.07 (m, 1H), 6.93 (d, J = 8.05 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H).
18. 3) δ 7.88 (d, J = 9.2 Hz, 1H), 7.16-7.25 (m, 3H), 7.05 (d, J = 6.6 Hz, 1H), 6.62-6.66 (m, 1H), 6.43 (d, J = 2.2 Hz, 1H), 4.02 (br s, 2H), 3.57 (s, 3H), 2.07 (s, 3H).
19. 3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.28-7.34 (m, 1H), 7.18 (dd, J = 7.3, 1.8 Hz, 1H), 6.97-7.03 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.62 (dd, J = 8.4, 2.2 Hz, 1H), 6.54 (d, J = 2.2 Hz, 1H), 3.8-4.2 (br s, 2H), 3.71 (s, 3H), 3.59 (s, 3H).
20. 3) δ 7.95 (d, J = 8.6 Hz, 1H), 7.08-7.23 (m, 3H), 6.95-7.03 (m, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.6 (s, 1H), 6.3 (s, 1H), 3.59 (s, 3H), 2.05 (s, 3H).
21. 3) δ 7.71 (d, J = 8.4 Hz, 1H), 7.27-7.33 (m, 1H), 7.16 (dd, J = 7.3, 1.8 Hz, 1H), 6.96-7.02 (m, 1H), 6.87 (d, J = 8.05 Hz, 1H), 6.77 (dd, J = 8.4, 2.6 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 5.84 (s, 1H), 3.69 (s, 3H), 3.62 (s, 3H).
22. 3) δ 7.99 (d, J = 8.8 Hz, 1H), 7.17-7.23 (m, 3H), 7.05 (d, J = 7.0 Hz, 1H), 6.84-6.97 (m, 5H), 6.76 (d, J = 2.9 Hz, 1H), 4.56-4.59 (m, 1H), 4.39 (dd, J = 11.4, 3.1 Hz, 1H), 4.19-4.30 (m, 3H), 3.60 (s, 3H), 2.06 (s, 3H).
23. 3) δ 7.90 (d, J = 8.8 Hz, 1H), 7.31-7.37 (m, 1H), 7.21 (dd, J = 7.3, 1.8 Hz, 1H), 7.00-7.05 (m, 1H), 6.84-6.94 (m 7H), 4.56-4.59 (m, 1H), 4.39 (dd, J = 11.35, 2.2 Hz, 1H), 4.17-4.25 (m, 3H), 3.71 (s, 3H), 3.63 (s, 3H).
24. 6) δ 12.19 (br s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.02-7.22 (m, 5H), 6.78-6.99 (m, 4H), 6.71 (d, J = 2.6 Hz, 1H), 4.52-4.59 (m, 1H), 4.25-4.42 (m, 3H), 4.12 (dd, J = 11.7, 7.3 Hz, 1H), 2.00 (s, 3H).
25. 6) δ 12.07 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.25-7.31 (m, 1H), 7.16 (dd, J = 7.7, 1.8 Hz, 1H), 6.78-7.02 (m, 8H), 4.54-4.57 (m, 1H), 4.41 (dd, J = 11.35, 2.2 Hz, 1H), 4.27-4.36 (m, 2H), 4.12 (dd, J = 11.7, 7.3 Hz, 1H), 3.62 (s, 3H).
26. 1H NMR consistent with that of 2.
27. 1H NMR consistent with that of 6.
28. 1H NMR consistent with that of 10.
29. 1H NMR consistent with that of 4.
30. 1H NMR consistent with that of 8.
31. 1H NMR consistent with that of 12.
32. 1H NMR identical to that of (S)-34.
33. 1H NMR identical to that of (S)-35.
34. 1H NMR identical to that of (S)-36.
35. 1H NMR identical to that of (S)-37.
36. 3) δ 7.93 (dd, J = 18.75, 8.8 Hz, 1H), 7.09-7.27 (m, 5H), 6.92 (dd, J = 8.8, 2.6 Hz, 1H), 6.75-6.84 (m, 4H), 6.63 (d, J = 2.6 Hz, 1H), 5.74 (d, J = 7.3 Hz, 1H), 4.47-4.55 (m, 2H), 4.32 (dd, J = 11.4, 2.35 Hz, 1H), 4.12-4.24 (m, 3H), 3.57 (s, 3H), 1.93-2.11 (m, 7H), 1.71-1.82 (m, 1H), 1.42-1.54 (m, 2H).
37. 3) δ 8.01 (d, J = 8.8 Hz, 1H), 7.20-7.32 (m, 4H), 6.99 (dd, J = 8.8, 2.6 Hz, 1H), 6.83-6.92 (m, 4H), 6.71 (d, J = 2.6 Hz, 1H), 5.81 (br s, 1H), 4.56-4.59 (m, 1H), 4.39 (dd, J = 11. 35, 2.2 Hz, 1H), 4.19-4.28 (m, 3H), 3.99 (d, J = 5.1 Hz, 2H), 3.65 (s, 3H), 2.12 (s, 3H).
38. 3) δ 8.05 (dd, J = 22.3, 8.8 Hz, 1H), 7.16-7.33 (m, 3H), 6.99 (dd, J = 88.8, 2.6 Hz, 1H), 6.83-6.92 (m, 5H), 6.70 (t, J = 2.2 Hz, 1H), 5.59 (br s, 1H), 4.37-4.60 (m, 3H), 4.08-4.31 (m, 3H), 3.63 (s, 3H), 2.05 (s, 3H), 0.92-1.26 (m, 3H), 0.74-0.80 (m, 6H).
39. 3) δ 7.78 (d, J = 8.4 Hz, 1H), 7.36-7.41 (m, 1H), 7.21 (d, J = 6.2 Hz, 1H), 6.83-7.03 (m, 7H), 6.76 (d, J = 2.6 Hz, 1H), 6.25 (br s, 1H), 4.55-4.68 (m, 2H), 4.39 (dd, J = 11.7, 2.6 Hz, 1H), 4.18-4.31 (m, 3H), 3.78 (s, 3H), 3.66 (s, 3H).
40. 3) δ 7.80 (d. J = 8.8 Hz, 1H), 7.26-7.39 (m, 1H), 7.23 (dd, J = 7.3, 1.8 Hz, 1H), 6.80-7.06 (m, 8H), 6.09 (br s, 1H), 4.53-4.58 (m, 1H), 4.26-4.31 (m, 1H), 4.11-4.24 (m, 3H), 3.94 (d, J = 5.1 Hz, 2H), 3.76 (s, 3H), 3.66 (s, 3H).
41. 3) δ 7.74 (d, J = 8.8 Hz, 1H), 7.27-7.33 (m, 1H), 7.13 (d, J = 2.05 Hz, 1H), 6.75-6.97 (m, 7H), 6.68 (d, J = 1.2 Hz, 1H), 5.94 (br s, 1H), 4.42-4.51 (m, 2H), 4.31 (dd, J = 11.4, 2.35 Hz, 1H), 4.08-4.23 (m, 3H), 3.69 (s, 3H), 3.56 (s, 3H), 0.96-1.37 (m, 3H), 0.67-0.73 (dd, J = 12.0, 6.4 Hz, 6H).
42. Sebti, S. M.; Hamilton, A. D.; Augeri, D. J.; Barr, K. J.; Donner, J. B.; Fakhoury, S. A.; O'Connor, S. J.; Rosenberg, S. H.; Shen, W.; Szczepankiewicz, B. G. U.S. patent 2002193596, 2002,Chem. Abstr. 2002, 138, 39539.
43. Bolchi C., Catalano P., Fumagalli L., Gobbi M., Pallavicini M., Pedretti A., Villa L., Vistoli G., and Valoti E. Bioorg. Med. Chem. 12 (2004) 4937
44. 3) δ 8.01 (d, J = 8.05 Hz, 1H), 7.83 (dd, J = 8.05, 1.8 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.18-7.31 (m, 3H), 7.06 (d, J = 7.3 Hz, 1H), 6.81-6.89 (m, 5H), 6.68 (t, J = 5.9 Hz, 1H), 4.37-4.42 (m, 1H), 4.32 (dd, J = 11.35, 2.2 Hz, 1H), 4.03 (dd, J = 11.35, 7.3 Hz, 1H), 3.82-3.88 (m, 1H), 3.65-3.75 (m, 1H), 3.63 (s, 3H), 2.06 (s, 3H).
45. 6) δ 12.83 (br s, 1H), 8.93 (t, J = 5.9 Hz, 1H), 7.88-7.96 (m, 2H), 7.71 (d, J = 1.1 Hz, 1H), 7.17-7.24 (m, 3H), 7.06 (d, J = 6.95 Hz, 1H), 6.77-6.86 (m, 4H), 4.28-4.34 (m, 2H), 3.96-4.00 (m, 1H), 3.51-3.57 (m, 2H), 2.01 (s, 3H).
46. 1H NMR consistent with that of 14.
47. 1H NMR consistent with that of 18.
48. 1H NMR consistent with that of 22.
49. 3) δ 7.90 (d, J = 7.7 Hz, 1H), 7.78 (dd, J = 8.1, 1.8 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.32-7.38 (m, 1H), 7.24-7.27 (m, 1H), 7.02-7.07 (m, 1H), 6.82-6.91 (m, 5H), 6.69 (br s, 1H), 4.30-4.40 (m, 2H), 4.00 (dd, J = 11.35, 6.95 Hz, 1H), 3.82-3.91 (m, 1H), 3.70 (s, 3H), 3.67 (s, 3H).
50. 6) δ 12.64 (br s, 1H), 8.93 (pseudo t, 1H), 7.78-7.90 (m, 3H), 7.25-7.35 (m, 2H), 6.98-7.04 (pseudo t, 1H), 6.78-6.87 (m, 4H), 4.29-4.35 (m, 2H), 3.95-4.01 (m, 1H), 3.64 (s, 3H), 3.52-3.60 (m, 2H).
51. 1H NMR consistent with that of 16.
52. 1H NMR consistent with that of 20.
53. 1H NMR consistent with that of 24.
54. 1H NMR identical to that of (S)-39.
55. 1H NMR identical to that of (S)-40.
56. 1H NMR identical to that of (S)-41.
57. 1H NMR identical to that of (S)-42.
58. 3) δ 7.95-8.03 (m, 1H), 7.82 (d, J = 8.05 Hz, 1H), 7.63 (s, 1H), 7.16-7.36 (m, 3H), 6.82-6.90 (m, 4H), 6.66-6.70 (m, 1H), 5.96-6.00 (m, 1H), 4.58-4.65 (m, 1H), 4.31-4.42 (m, 2H), 4.01 (dd, J = 11.35, 7.3 Hz, 1H), 3.84-3.93 (m, 1H), 3.69-3.75 (m, 1H), 3.66 (s, 3H), 1.99-2.17 (m, 8H), 1.82-1.89 (m, 1H), 1.59-1.65 (m, 1H).
59. 3) δ 8.02 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.2, 1.8 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.19-7.33 (m, 4H), 6.82-6.90 (m, 4H), 6.67 (br s, 1H), 5.95 (br s, 1H), 4.38-4.41 (m, 1H), 4.33 (dd, J = 11.4, 2.3 Hz, 1H), 4.01 (dd, J = 11.4, 7.3 Hz, 1H), 3.91 (d, J = 5.3 Hz, 2H), 3.85-3.88 (m, 1H), 3.68-3.75 (m, 1H), 3.66 (s, 3H), 2.11 (s, 3H).
60. 3) δ 7.99-8.05 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.1, 1.8 Hz, 1H), 7.63 (s, 1 H), 7.15-7.33 (m, 4H), 6.81-6.89 (m, 4H), 6.73 (t, J = 5.9 Hz, 1H), 5.76 (d, J = 7.7 Hz, 1H), 4.31-4.42 (m, 3H), 3.97-4.03 (m, 1H), 3.83-3.92 (m, 1H), 3.66-3.75 (m, 1H), 3.64 (s, 3H), 2.05 (s, 3H), 1.25-1.33 (m, 1H), 0.97-1.06 (m, 2H), 0.76 (pseudo t, 6H).
61. 3) δ 7.79 (d, J = 0.7 Hz, 1H), 7.65 (d, J = 1.1 Hz, 1H), 7.37-7.43 (m, 1H), 7.22 (d, J = 6.6 Hz, 1H), 7.01-7.07 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.81-6.89 (m, 3H), 6.70 (m, 1H), 6.50 (br s, 1H), 4.63-4.68 (m, 1H), 4.30-4.39 (m, 2H), 3.96-4.10 (m, 1H), 3.82-3.90 (m, 1H), 3.77 (s, 3H), 3.69-3.75 (m, 1H), 3.66 (s, 3H), 1.87-2.16 (m, 5H), 1.65-1.67 (m, 2H).
62. 3) δ 7.69-7.76 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H), 7.28-7.34 (m, 1H), 7.17 (dd, J = 6.95, 1.8 Hz, 1H), 6.94-6.99 (m, 1H), 6.82-6.88 (m, 1H), 6.74-6.81 (m, 4H), 6.63 (t, J = 5.9 Hz, 1H), 6.21 (t, J = 4.8 Hz, 1H), 4.23-4.34 (m, 2H), 3.75-4.05 (m, 4H), 3.68 (s, 3H), 3.60 (s, 3H).
63. 3) δ 7.73 (d, J = 8.05 Hz, 1H), 7.78 (dd, J = 8.05, 1.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.36-7.42 (m, 1H), 7.20-7.23 (m, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.91-6.96 (m, 4H), 6.65 (br s, 1H), 6.20 (br s, 1H), 4.51-4.57 (m, 1H), 4.30-4.39 (m, 2H), 3.97-4.03 (m, 1H), 3.83-3.91 (m, 1H), 3.75 (s, 3H), 3.65-3.73 (m, 1H), 3.64 (s, 3H), 1.33-1.37 (m, 1H), 1.09-1.16 (m, 2H), 0.74-0.80 (2 d, 6H).
64. 50) was calculated by linear regression analysis of the logarithm of the concentration versus logit by using the SigmaPlot 8.0 software.
65. 4, 1 μg/ml Aprotinin, 1 μg/ml Leupeptin and 1 μg/ml Pepstatin) for 30 min on ice. Cell lysates were cleared by centrifugation at 15,000 g for 10 min, and protein concentrations were determined using the BCA protein assay (Pierce). Lysates were separated by SDS-PAGE under reducing conditions, transferred to Immobilon PVDF (Millipore) and subsequently immunoblotted with anti Ras antibody (Upstate), prior to visualization by enhanced chemiluminescence (ECL, Amersham Corp.) (Ferri, N.; Colombo, G.; Ferrandi, C.; Raines, E.W.; Levkau, B.; Corsini, A. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1043).
66. Human aortic SMCs express all three isoforms of Ras (H-Ras, K-Ras, and N-Ras). The antibody utilized for the detection of Ras by western blotting analysis recognizes all three isoforms and therefore the isoform specific effect of 1 on Ras prenylation could not be studied. Nonetheless, the almost complete inhibition of Ras prenylation by 1 indicates that all three isoforms were affected by this compound.
67. 50 value for these compounds.