Optimizing thiadiazole analogues of resveratrol versus three chemopreventive targets

Abstract

Chemoprevention is an approach to decrease cancer morbidity and mortality through inhibition of carcinogenesis and prevention of disease progression. Although the trans stilbene derivative resveratrol has chemopreventive properties, its action is compromised by weak non-specific effects on many biological targets. Replacement of the stilbene ethylenic bridge of resveratrol with a 1,2,4-thiadiazole heterocycle and modification of the substituents on the two aromatic rings afforded potential chemopreventive agents with enhanced potencies and selectivities when evaluated as inhibitors of aromatase and NF-κB and inducers of quinone reductase 1 (QR1).

Synthesis, antioxidant and anticancer screenings of berberine–indole conjugates

“…It is worthwhile to assume that compounds bearing functional groups demonstrating potential antioxidant effects could be studied further to investigate their efficacy as chemopreventive and chemotherapeutic agents. To further support this statement, researchers have reported several molecules with antioxidant and chemopreventive properties, including compounds bearing phenolic hydroxyl group(s) [11,12,13] and compounds containing heterocyclic systems such as imidazole [14,15], thiazole [16], and thiadiazole [17,18].…”

Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer

“…In comparison to trans-resveratrol, the pyridyl derivatives 71 and 72 (Fig.12.) had 30-125 times higher aromatase inhibition, with IC 50 s = 0.2 µM and 0.8 µM, respectively. [82] Hoshino et al synthesized five resveratrol sulfate metabolites and assessed them for aromatase inhibition. Resveratrol and its sulfates were weak AIs; the most active compound in this series was sulfate metabolite 73 ( Fig.12.…”

Optimization of thiazole analogues of resveratrol for induction of NAD(P)H:quinone reductase 1 (QR1)

“…The resveratrol trans-stilbene double bond was previously replaced with a thiadiazole ring. 45 This strategy afforded the lead compound 2 (Figure 1), which had good QR1 induction activity with a CD value 10 times lower than resveratrol. 45 In addition to the QR1 induction activity, compound 2 also had weak activities as an aromatase inhibitor and as an inhibitor of NF-κB.…”

“…45 This strategy afforded the lead compound 2 (Figure 1), which had good QR1 induction activity with a CD value 10 times lower than resveratrol. 45 In addition to the QR1 induction activity, compound 2 also had weak activities as an aromatase inhibitor and as an inhibitor of NF-κB. 45 Further chemical optimization of the lead compound 2 furnished 3,5-bis(2-fluorophenyl)-1,2,4-thiadiazole ( 3 ), which exhibits a higher QR1 induction ratio and lower CD value (IR 10.5; CD = 1.8 μM, Figure 1), and high target selectivity.…”