Design of Cytochrome P450 1B1 Inhibitors via a Scaffold-Hopping Approach

Abstract

Cytochrome P450 1B1 (CYP1B1) is a potential drug target in cancer research that is overexpressed in several solid tumors but is present only at low levels in healthy tissues. Its expression is associated with resistance to common chemotherapeutics, while inhibitors restore efficacy to these drugs in model systems. The majority of CYP1B1 inhibitors are derived from a limited number of scaffolds, and few have achieved outstanding selectivity against other human CYPs, which could impede clinical development. This study explores a new chemical space for CYP1B1 inhibitors using a scaffold-hopping approach and establishes 2,4-diarylthiazoles as a promising framework for further development. From a small library, compound 15 emerged as the lead, with picomolar CYP1B1 inhibition, and over 19,000-fold selectivity against its relative, CYP1A1. To investigate the activity of 15, molecular dynamics, optical spectroscopy, point mutations, and traditional structure–activity relationships were employed and revealed key interactions important for the development of CYP1B1 inhibitors.

Base-Promoted Annulated Aromatization of Aryl Acetylenes with Dimethyl Sulfoxide to Access Symmetrical/Unsymmetric m-Terphenyl

“…3,3′′,5,5′′-tetramethyl-1,1′:3′,1′′-terphenyl (Scheme 2, 3k, Known Compound). 28 Compound 3k was synthesized on the basis of general procedure 1 and purified by column chromatography with PE as the eluent: 78 mg, 51% yield, white solid; 1 H NMR (400 MHz, CDCl 3 ) δ7.76 (s, 1H), 7.56 (dd, J = 6.9, 1.8 Hz, 2H), 7.49 (dd, J = 8.6, 6.5 Hz, 1H), 6.78 (d, J = 2.3 Hz, 4H), 6.50 (t, J = 2.3 Hz, 2H), 3.86 (s, 12H). 13 4a Compound 3l was synthesized on the basis of general procedure 1 and purified by column chromatography with PE as the eluent: 69 mg, 62% yield, yellow solid; 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (s, 1H), 7.62 (s, 2H), 7.57−7.49 (m, 5H), 7.42−7.33 (m, 4H).…”

Design of Novel 2-Phenylquinazolin-4-amines as Selective CYP1B1 Inhibitors for Overcoming Paclitaxel Resistance in A549 Cells

“…In a recent breakthrough in 2022, Zhang and collaborators reported the discovery of N -aryl-2,4-bithiazole-2-amine ( 1c ) as a potent and specific CYP1B1 inhibitor, which was capable of successfully reversing paclitaxel resistance in A549 cells . Additionally, Glazer et al employed a scaffold-hopping approach to develop 2,4-diarylthiazole (CYP1B1 inhibitor 1d ), which exhibited substantial inhibition and remarkable selectivity toward CYP1B1, boasting a selectivity index (SI, 1A1/1B1) as high as 19900 . Ge et al.…”

“…35 Additionally, Glazer et al employed a scaffoldhopping approach to develop 2,4-diarylthiazole (CYP1B1 inhibitor 1d), which exhibited substantial inhibition and remarkable selectivity toward CYP1B1, boasting a selectivity index (SI, 1A1/1B1) as high as 19900. 36 Ge et al identified 4′trifluoromethylchalcones as potent and selective inhibitors of hCYP1B1 that do not activate AhR. 37 Despite these impressive achievements, there remains a need for the development of CYP1B1 inhibitors with enhanced water solubility and selectivity to pave the way for future use in clinical applications.…”

“…Glazer et al designed the CYP1B1 inhibitor 1d by substituting the alkene moiety of TMS with πexpansion system thiazole and introducing a nitrile group that readily forms hydrogen bonds. 36 A notable observation is that both quinazolinone and flavonoid CYP1B1 inhibitors share a common structural feature, comprising aromatic rings and a nonaromatic B-ring, as depicted in Figure 1. As a result, we hypothesized that these inhibitors could be enhanced by aromatizing the B-ring and introducing heteroatoms to facilitate hydrogen bonding, as illustrated in Figure 2.…”

“…Molecular docking analyses revealed that the interaction between these inhibitors and CYP1B1 primarily involves π–π stacking and hydrogen bonding interactions. , In particular, the presence of conjugated electron-donating methoxy groups in compound 1a heightens the electron density within the aromatic ring, thereby intensifying the π–π stacking interaction with Phe 231 . Glazer et al designed the CYP1B1 inhibitor 1d by substituting the alkene moiety of TMS with π-expansion system thiazole and introducing a nitrile group that readily forms hydrogen bonds . A notable observation is that both quinazolinone and flavonoid CYP1B1 inhibitors share a common structural feature, comprising aromatic rings and a nonaromatic B-ring, as depicted in Figure .…”