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. Author manuscript; available in PMC: 2020 Dec 12.
Published in final edited form as: J Med Chem. 2019 Nov 26;62(23):10645–10663. doi: 10.1021/acs.jmedchem.9b00966

Table 4.

Increased Toxicity of Paclitaxel in the Presence of Rationally Designed P-gp Inhibitorsa

inhibitor concentration resensitization to paclitaxel with the indicated treatment and fold-increased sensitivity in the presence of inhibitors
PTX alone PTX + 29 PTX + 238 PTX + 255 PTX + 278 PTX + 280 PTX + 286
IC50 PTX (nM) IC50 PTX (nM) fold vs PTX fold vs PTX + 29 IC50 PTX (nM) fold vs PTX fold vs PTX + 29 IC50 PTX (nM) fold vs PTX fold vs PTX + 29 IC50 PTX (nM) fold vs PTX fold vs PTX + 29 IC50 PTX (nM) fold vs PTX fold vs PTX + 29 IC50 PTX (nM) fold vs PTX fold vs PTX + 29
3 μM 2120 629 3 1 185 11 3.4 172 12 3.7 231 9.2 2.7 160 13 3.9 458 4.6 1.4
5 μM 2120 194 11 1 1.9 1116 102 34 372 5.7 109 19 1.8 56 38 3.5 379 5.6 0.5
7 μM 2120 59 36 1 0.64 3312 92 2.9 731 20 21 101 2.8 16 133 3.7 192 11 0.3
10 μM 2120 21 101 1 0.07 30,286 300 0.78 2118 27 13 163 1.6 11 193 1.9 131 16 0.2
a

Cytotoxicity of the chemotherapeutic paclitaxel (PTX) in P-gp-overexpressing prostate cancer cells, DU145TXR, was determined in the absence and presence of the structural 29-variants, 238, 255, 276, 280, and 286. For each experimental compound, (a) IC 50 values of PTX alone or in the presence of inhibitors (in nM), (b) fold improvement of PTX sensitivity in the presence of an inhibitor, and (c) fold improvement of PTX sensitivity by variants compared to parental compound 29 are given.