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. Author manuscript; available in PMC: 2016 Aug 1.
Published in final edited form as: Curr Med Chem. 2016;23(3):201–241. doi: 10.2174/0929867323666151127201829

Table 11.

Cytotoxicity,a metabolic stability,b and mouse toxicityc of PAC-1 analogues.

graphic file with name nihms801440u9.jpg
Compound R1 R2 R3 U-937 72h IC50 (μM) RLM 3h %Stability Mouse Toxicity IP 200 mg/kg (* = 100 mg/kg)
PAC-1 (1) Bn H All 10.2 ± 0.3 38 ± 2 Severe
14a 4-F-Bn H All 11.1 ± 2.1 31 ± 1 N.D.
S-PAC-1 (37) 4-SO2NH2-Bn H All 8.9 ± 0.6 84 ± 1 None
38 Bz H All 12.1 ± 1.3 89 ± 4 N.D.
39 4-CN-Bn H All 13.7 ± 0.9 48 ± 2 N.D.
40 4-CN-Bz H All 13.1 ± 3.7 90 ± 4 N.D.
41 4-F-Bz H All 10.2 ± 1.7 86 ± 2 Moderate
42 4-CF3-Bn H All 15.3 ± 6.7 16 ± 1 N.D.
43 4-CF3-Bz H All 6.6 ± 1.9 85 ± 6 Lethal*
44 Bn H n-Pr 9.6 ± 2.1 30 ± 1 N.D.
45 4-SO2NH2-Bn H n-Pr 4.9 ± 0.4 61 ± 2 N.D.
46 Bz H n-Pr 9.4 ± 1.3 71 ± 3 N.D.
47 4-CN-Bn H n-Pr 9.0 ± 1.2 30 ± 2 N.D.
48 4-CN-Bz H n-Pr 12.8 ± 2.7 61 ± 3 N.D.
49 4-F-Bn H n-Pr 10.0 ± 1.7 24 ± 2 N.D.
50 4-F-Bz H n-Pr 7.3 ± 0.9 69 ± 4 N.D.
51 4-CF3-Bn H n-Pr 4.1 ± 0.4 15 ± 2 N.D.
52 4-CF3-Bz H n-Pr 4.8 ± 1.2 64 ± 1 Lethal*
53 Bn F H 17.0 ± 1.4 64 ± 4 N.D.
54 4-SO2NH2-Bn F H N.D. N.D. N.D.
55 Bz F H 15.7 ± 2.6 88 ± 1 N.D.
56 4-CN-Bn F H N.D. N.D. N.D.
57 4-CN-Bz F H 15.3 ± 1.3 88 ± 4 N.D.
58 4-F-Bn F H N.D. N.D. N.D.
59 4-F-Bz F H 15.3 ± 0.8 86 ± 2 N.D.
60 4-CF3-Bn F H 4.7 ± 0.3 30 ± 5 N.D.
61 4-CF3-Bz F H 8.7 ± 0.5 87 ± 3 Moderate
62 Bn F All 9.5 ± 0.9 56 ± 1 N.D.
63 4-SO2NH2-Bn F All 9.8 ± 1.3 89 ± 3 Lethal
64 Bz F All 8.6 ± 2.0 93 ± 7 Moderate
65 4-CN-Bn F All 12.7 ± 2.0 65 ± 2 N.D.
66 4-CN-Bz F All 10.1 ± 2.0 95 ± 4 Mild
67 4-F-Bn F All 10.3 ± 4.1 57 ± 1 N.D.
68 4-F-Bz F All 8.5 ± 1.4 92 ± 3 Severe
69 4-CF3-Bn F All 3.4 ± 0.6 49 ± 3 N.D.
70 4-CF3-Bz F All 6.5 ± 0.6 90 ± 2 Moderate
71 Bn F n-Pr 8.9 ± 1.2 49 ± 6 N.D.
72 4-SO2NH2-Bn F n-Pr 8.7 ± 0.4 62 ± 3 N.D.
73 Bz F n-Pr 12.3 ± 1.0 86 ± 5 N.D.
74 4-CN-Bn F n-Pr 11.2 ± 0.9 49 ± 5 N.D.
75 4-CN-Bz F n-Pr 9.4 ± 1.2 66 ± 3 Mild
76 4-F-Bn F n-Pr 7.5 ± 0.7 48 ± 1 N.D.
77 4-F-Bz F n-Pr 7.5 ± 1.4 67 ± 3 Severe
78 4-CF3-Bn F n-Pr 3.9 ± 0.6 40 ± 1 N.D.
79 4-CF3-Bz F n-Pr 5.2 ± 0.6 64 ± 5 Lethal

N.D. = not determined.

a

Cells treated with compounds for 72 hours. Biomass quantified by sulforhodamine B assay. IC50 values shown are mean ± s.e.m. (n = 3).

b

Rat liver microsomes treated with compounds (10 μM) for 3 hours. Percent stability values shown are mean ± s.e.m. (n = 3).

c

Mice dosed with compound via i.p. injection at 200 mg/kg (except *100 mg/kg). [50]