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. Author manuscript; available in PMC: 2009 Nov 13.
Published in final edited form as: J Med Chem. 2008 Oct 11;51(21):6853–6865. doi: 10.1021/jm800967h

Table 3.

Physicochemical, in vitro and modelling parameters for TPZ and TTOs 33–42.

graphic file with name nihms91083f18.jpg
No R1 R2 pKaa logP7 calcb.4 Sol.c mM E(1) mV HT29IC50 hypox μM HT29 HCRd SiHa IC50 hypox μM SiHa HCRd D calce,f kmetf,g min−1 X½f,h μm AUCreqi μM.min HCDj
1k nal nal nal −0.33 9 −456 5.1 71 2.5 107 4.2 0.58 45 10200 4.1
33 CH3 CH2OH 0.0 1.14 10 13.0 80 8.0 104 21.0 0.24 158 10300 10.9
34 CH3 CH2N-morpholine 7.1 0.99 36 2.9 72 1.7 134 21.0 0.96 80 4960 5.8
35 CH2OH H 0.0 0.69 5 −452 17 45 6.5 48 17.7 0.47 104 4150 9.2
36 CH2N-morpholine H 7.0 0.29 43 4.8 31 2.4 62 17.3 0.54 96 3390 8.8
37 CH2OH CH2N-morpholine 7.1 −0.18 48 −408 2.4 121 1.8 206 3.8 0.90 35 14100 2.7
38 (CH2)2OH H na 0.50 2 7.7 102 2.9 86 15.4 0.54 91 6130 8.6
39 (CH2)3N-morpholine H 7.5 0.50 >51 −431 3.6 36 1.3 84 18.5 0.54 100 2560 8.7
40 graphic file with name nihms91083t15.jpg CH2N-morpholine 7.1 −1.30 51 −468 8.9 25 5.1 43 3.5 0.31 57 6680 5.7
41 graphic file with name nihms91083t16.jpg H 5.8 0.09 >47 −344 13.1 2 3.1 6 20.9
42 graphic file with name nihms91083t17.jpg H 5.2 0.19
a

Calculated using ACD pKa.

b

Calculated using ACD logD.

c

Solubility of HCl salts in culture medium.

d

Hypoxia Cytotoxicity Ratio = oxic IC50/hypoxic IC50.

e

Diffusion coefficient in HT29 MCLs ×10−7 cm2s−1.

f

Error estimates are provided in the Supporting Information.

g

First order rate constant for metabolism in anoxic HT29 cell suspensions, scaled to the cell density in MCLs.

h

Penetration half distance in anoxic HT29 tumor tissue (see text).

i

Predicted area under the plasma concentration-time curve required to give 1 log of cell kill in addition to that produced by a single 20 Gy dose of gamma radiation.

j

In vivo Hypoxic Cytotoxicity Differential = LCKhypoxic/LCKoxic.

k

Data from Reference 48.

l

Not applicable.