Table 1 Novel potent and highly selective nNOS inhibitors.

From: Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS)

Compounds

Ki (µM)

Selectivitya

Cytotoxicity (IC50 from 3 melanoma cell linesb) (µM)

Cytotoxicity (IC50 from 3 immortal melanocyte cell linesc)

nNOS

iNOS

eNOS

nNOS/iNOS

nNOS/eNOS

HH04422

0.005

1.7

2.7

340

540

5.27 ± 3.3

4.25 ± 1.67NS

MAC-3-19023

0.033

4.5

3.9

138

119

1.21 ± 0.19

1.95 ± 0.87NS

  1. All the NOS isozymes used were recombinant enzymes overexpressed in E. coli. Ki values are calculated directly using known literature methods and detailed in previously published manuscripts22,23,24,25,26. Cytotoxic effects of nNOS inhibitors in human melanoma were detected by MTT colorimetric analysis and compared to that of human immortal melanocytes24,27. The IC50 values are the average of three cell lines.
  2. aSelectivity of nNOS over iNOS or eNOS was calculated as described previously.
  3. bThree human melanoma cell lines: A375—metastatic, BRAFV600E; Sk-Mel-28—metastatic, BRAFV600E; wm3211—primary, BRAFwt.
  4. cThree human immortal melanocyte cell lines: Hermes 1, Hermes 3a and Hermes 4a.
  5. NSNo statistical difference compared to IC50s of melanoma cells lines.
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