Improving the solubility of anti-proliferative thieno[2,3-b]quinoline-2-carboxamides

Disruption of Crystal Packing in Thieno[2,3-b]pyridines Improves Anti-Proliferative Activity

“…For the remaining analogues, the decreased melting point was indicative of decreased crystal packing, and consequently, improved solubility. NMR experiments were performed with samples dissolved in DMSO-d6 so as to be consistent with previously obtained spectra for the thieno[2,3- b ]pyridines [ 1 , 20 ].…”

“…It is important to note that the parent alcohols and their derivatives do contain a chiral centre at the carbonyloxy substituent, however, the alcohols have been previously tested racemically, and molecular modelling studies have shown that both the ( R )- and ( S )-enantiomers are likely to bind to the PI–PLC active site [ 1 ]. The results of this study by Haverkate et al showed that the most active 2′-Me-3′-Cl and 1′-naphthyl substituted alcohols had IC 50 values of 72–171 nM, higher than their derivatives [ 1 ]. The activity of the novel ‘prodrug-like’ derivatives was therefore improved when compared to the parent alcohols.…”

“… * denotes previously tested parent alcohol-containing thienopyridines [ 1 ]. The most active compounds are shown in the highlighted rows …”

“…The potent anti-proliferative activity of alcohol-containing thieno[2,3- b ]pyridines, such as those shown in Figure 1 , has been reported [ 1 ]. The parent thieno[2,3- b ]pyridines were initially developed as PI-PLC inhibitors following their discovery through vHTS in 2009 [ 2 ], after which structure refinement led to the synthesis of various analogue series that have demonstrated excellent anti-proliferative activity against MDA-MB-231 and HCT-116 cancer cells, with the best compounds exhibiting IC 50 values in the nM range [ 1 , 3 ].…”

“…The following supporting information can be downloaded online, Refs. [ 1 , 26 ] are cited in the Supplementary Materials. Figure S1: 1 H NMR spectrum of 6a (400 MHz; DMSO- d 6 ), Figure S2: 13 C NMR spectrum of 6a (100 MHz; DMSO- d 6 ), Figure S3: 1 H NMR spectrum of 6b (400 MHz; DMSO- d 6 ), Figure S4: 13 C NMR spectrum of 6b (100 MHz; DMSO- d 6 ), Figure S5: 1 H NMR spectrum of 6c (400 MHz; DMSO- d 6 ), Figure S6: 13 C NMR spectrum of 6c (100 MHz; DMSO- d 6 ), Figure S7: 1 H NMR spectrum of 6d (400 MHz; DMSO- d 6 ), Figure S8: 13 C NMR spectrum of 6d (100 MHz; DMSO- d 6 ), Figure S9: 1 H NMR spectrum of 6e (400 MHz; DMSO- d 6 ), Figure S10: 13 C NMR spectrum of 6e (100 MHz; DMSO- d 6 ), Figure S11: 1 H NMR spectrum of 7a (400 MHz; DMSO- d 6 ), Figure S12: C NMR spectrum of 7a (100 MHz; DMSO- d 6 ), Figure S13: 1 H NMR spectrum of 7b (400 MHz; DMSO- d 6 ), Figure S14: 13 C NMR spectrum of 7b (100 MHz; DMSO- d 6 ), Figure S15: 1 H NMR spectrum of 7c (400 MHz; DMSO- d 6 ), Figure S16: 13 C NMR spectrum of 7c (100 MHz; DMSO- d 6 ), Figure S17: 1 H NMR spectrum of 7d (400 MHz; DMSO- d 6 ), Figure S18: 13 C NMR spectrum of 7d (100 MHz; DMSO- d 6 ), Figure S19: 1 H NMR spectrum of 7e (400 MHz; DMSO- d 6 ), Figure S20: 13 C NMR spectrum of 7e (100 MHz; DMSO- d 6 ), Figure S21: 1 H NMR spectrum of 8a (400 MHz; DMSO- d 6 ), Figure S22: 13 C NMR spectrum of 8a (100 MHz; DMSO- d 6 ), Figure S23: 1 H NMR spectrum of 8b (400 MHz; DMSO- d 6 ), Figure S24: 13 C NMR spectrum of 8b (100 MHz; DMSO- d 6 ), Figure S25: 1 H NMR spectrum of 8c (400 MHz; DMSO- d 6 ), Figure S26: 13 C NMR spectrum of 8c (100 MHz; DMSO- d 6 ), Figure S27: 1 H NMR spectrum of 8d (400 MHz; DMSO- d 6 ), Figure S28: 13 C NMR spectrum of 8d (100 MHz; DMSO- d 6 ), Figure S29: 1 H NMR spectrum of 8e (400 MHz; DMSO- d 6 ), Figure S30: 13 C NMR spectrum of 8e (100 MHz; DMSO- d 6 ), Figure S31: HRMS of 6a (top) and 6b (bottom), Figure S32: HRMS of 6c (top) and 6d (bottom), Figure S33: HRMS of 6e (top) and 7a (bottom), Figure S34: HRMS of 7b (top) and 7c (bottom), Figure S35: HRMS of 7d (top) and 7e (bottom), Figure S36: HRMS of 8a (top) and 8b (bottom), Figure S37: HRMS of 8c (top) and 8d (bottom), Figure S38: HRMS of 8e , Figure S39:...…”