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

Cytochrome P450 1B1 (CYP1B1) contributes to the metabolic inactivation of chemotherapeutics when overexpressed in tumor cells. Selective inhibition of CYP1B1 holds promise for reversing drug resistance. In our pursuit of potent CYP1B1 inhibitors, we designed and synthesized a series of 2-phenylquinazolin-4-amines. A substantial proportion of these newly developed inhibitors demonstrated inhibitory activity against CYP1B1, accompanied by improved water solubility. Remarkably, compound 14b exhibited exceptional inhibitory efficacy and selectivity toward CYP1B1. Molecular docking studies suggested that the expansion of the π-system through aromatization, the introduction of an amine group, and iodine atom augmented the binding affinity. Furthermore, inhibitors 14a, 14b, and 14e demonstrated the ability to significantly reduce the resistance in A549 cells to paclitaxel, while also inhibiting the migration and invasion of these cells. Finally, radioiodine labeling experiments shed light on the metabolic pathway of compound 5l in mice, highlighting the potential of 125I-5l as a radioactive probe for future research endeavors.

Design, Synthesis, and Evaluation of 18F-Labeling CYP1B1 PET Tracer Based on 2-Phenylquinazolin.

Cytochrome P450 (CYP)1B1 has been identified to be specifically overexpressed in several solid tumors, thus it's a potential target for the detection of tumors. Based on the 2-Phenylquinazolin CYP1B1 inhibitors, we designed and synthesized several positron emission computed tomography (PET) imaging probes targeting CYP1B1. Through IC50 determinations, most of these probes exhibited good affinity and selectivity to CYP1B1. Considering their affinity, solubility, and their 18F labeling methods, we chose compound 5c as the best candidate. The 18F radiolabeling of [18F] 5c was easy to handle with good radiolabeling yield and radiochemical purity. In vitro and in vivo stability study indicated that probe [18F]5c has good stability. In cell binding assay, [18F]5c could be specifically taken up by tumor cells, especially HCT-116 cells. Although the tumor-blood (T/B) and tumor-muscle (T/M) values and PET imaging results were unsatisfied, it is still possible to develop PET probes targeting CYP1B1 by structural modification on the basis of 5c in the future.

Development of [18F]Thiazolylacylaminopyridine-Based Glycogen synthase Kinase-3ß ligands for positron emission tomography imaging.

Glycogen synthase kinase-3ß (GSK-3ß) regulates numerous of CNS-specific signaling pathways, and is particularly implicated in various pathogenetic mechanisms of Alzheimer's disease (AD). A noninvasive method for detecting GSK-3ß in AD brains via positron emission tomography (PET) imaging could enhance the understanding of AD pathogenesis and aid in the development of AD therapeutic drugs. In this study, an array of fluorinated thiazolyl acylaminopyridines (FTAAP) targeting GSK-3ß were designed and synthesized. These compounds showed moderate to high affinities (IC50 = 6.0 - 426 nM) for GSK-3ß in vitro. A potential GSK-3ß tracer, [18F]8, was successfully radiolabeled. [18F]8 had unsatisfactory initial brain uptake despite its suitable lipophilicity, molecular size and good stability. Further structural refinement of the lead compound is needed to develop promising [18F]-labeled radiotracers for the detection of GSK-3ß in AD brains.

Gas-phase formation of Grignard-type organolanthanide (III) ions RLnCl3 - : The influences of lanthanide center and hydrocarbyl group.

RATIONALE: Compared with organomagnesium compounds (Grignard reagents), the Grignard-type organolanthanides (III) exhibit several utilizable differences in reactivity. However, the fundamental understanding of Grignard-type organolanthanides (III) is still in its infancy. Decarboxylation of metal carboxylate ions is an effective method to obtain organometallic ions that are well suited for gas-phase investigation using electrospray ionization (ESI) mass spectrometry in combination with density functional theory (DFT) calculations. METHODS: The (RCO2 )LnCl3 - (R = CH3 , Ln = La-Lu except Pm; Ln = La, R = CH3 CH2 , CH2 CH, HCC, C6 H5 , and C6 H11 ) precursor ions were produced in the gas phase via ESI of LnCl3 and RCO2 H or RCO2 Na mixtures in methanol. Collision-induced dissociation (CID) was employed to examine whether the Grignard-type organolanthanide (III) ions RLnCl3 - can be obtained via decarboxylation of lanthanide chloride carboxylate ions (RCO2 )LnCl3 - . DFT calculations can be used to determine the influences of lanthanide center and hydrocarbyl group on the formation of RLnCl3 - . RESULTS: When R = CH3 , CID of (CH3 CO2 )LnCl3 - (Ln = La-Lu except Pm) yielded decarboxylation products (CH3 )LnCl3 - and reduction products LnCl3 ·- with a variation in the relative intensity ratio of (CH3 )LnCl3 - /LnCl3 ·- . The trend is as follows: (CH3 )EuCl3 - /EuCl3 ·- < (CH3 )YbCl3 - /YbCl3 ·- ≈ (CH3 )SmCl3 - /SmCl3 ·- < other (CH3 )LnCl3 - /LnCl3 ·- , which complies with the trend of Ln (III)/Ln (II) reduction potentials in general. When Ln = La and hydrocarbyl groups were varied as CH3 CH2 , CH2 CH, HCC, C6 H5 , and C6 H11 , the fragmentation behaviors of these (RCO2 )LaCl3 - precursor ions were diverse. Except for (C6 H11 CO2 )LaCl3 - , the four remaining (RCO2 )LaCl3 - (R = CH3 CH2 , CH2 CH, HCC, and C6 H5 ) ions all underwent decarboxylation to yield RLaCl3 - . (CH2 CH)LaCl3 - and especially (CH3 CH2 )LaCl3 - are prone to undergo ß-hydride transfer to form LaHCl3 - , whereas (HCC)LaCl3 - and (C6 H5 )LaCl3 - are not. A minor reduction product, LaCl3 ·- , was formed via C6 H5 radical loss of (C6 H5 )LaCl3 - . The relative intensities of RLaCl3 - compared to (RCO2 )LaCl3 - decrease as follows: HCC > CH2 CH > C6 H5 > CH3 > CH3 CH2 >> C6 H11 (not visible). CONCLUSION: A series of Grignard-type organolanthanide (III) ions RLnCl3 - (R = CH3 , Ln = La-Lu except Pm; Ln = La, R = CH3 CH2 , CH2 CH, HCC, and C6 H5 ) were produced from (RCO2 )LnCl3 - via CO2 loss, whereas (C6 H11 )LaCl3 - did not. The experimental and theoretical results suggest that the reduction potentials of Ln (III)/Ln (II) couples as well as the bulkiness and hybridization of hydrocarbyl groups play important roles in promoting or limiting the formation of RLnCl3 - via decarboxylation of (RCO2 )LnCl3 - .

Dual-Ligand Strategy for the Preparation of Gas-Phase Uranyl(VI) Benzyne Complexes from Uranyl(VI) Benzoates.

The uranyl(VI) benzyne complex (η2-C6H4)UO2Cl- was prepared in the gas phase by electrospray ionization mass spectrometry coupled with collision-induced dissociation. It was formed via a dual-ligand strategy that requires the elimination of benzoic acid or benzene/CO2 from the uranyl dibenzoate precursor (C6H5CO2)2UO2Cl-. This contrasts the known strategy for the formation of gas-phase benzyne complexes that would result from CO2/HCl elimination from (C6H5CO2)UO2Cl2-, during which only one benzoate ligand is involved. Such dual-ligand strategy can be extended to the preparation of a series of methyl- and halo-substituted benzyne complexes of uranyl(VI). Density functional theory calculations at the B3LYP level reveal that the benzyne complex (η2-C6H4)UO2Cl- features a metallacyclopropene structure with the C6H42- ligand coordinated to uranium(VI) through two polarized U-Cbenzyne σ bonds, in accordance with the reactivity test toward water. Dehydrochlorination of the benzyne complex (η2-C6H4)UO2Cl- from (C6H5)UO2Cl2- that originates from decarboxylation of (C6H5CO2)UO2Cl2- with a single benzoate ligand is neither kinetically nor thermodynamically favorable than simple C6H5 radical loss to give UVO2Cl2-. This arises from the presence of an accessible V oxidation state for uranium and accounts for the necessity for the dual-ligand strategy in the preparation of uranyl(VI) benzyne complexes from uranyl benzoate precursors.

A new class of CYP1B1 inhibitors derived from bentranil.

Cytochrome P450 1B1 (CYP1B1) is highly expressed in a variety of tumors and implicated to drug resistance. More and more researches have suggested that CYP1B1 is a new target for cancer prevention and therapy. Various CYP1B1 inhibitors with a rigid polycyclic skeleton have been developed, such as flavonoids, trans-stilbenes, and quinazolines. To obtain a new class of CYP1B1 inhibitors, we designed and synthesized a series of bentranil analogues, moreover, IC50 determinations were performed for CYP1B1 inhibition of five of these compounds and found that 6o and 6q were the best inhibitors, with IC50 values in the nM range. The selectivity index (SI) of CYP1B1 over CYP1A1 and CYP1A2 was 30-fold higher than that of α-naphthoflavone (ANF). The molecular docking results showed that compound 6q fitted better into the CYP1B1 binding site than other compounds, which was consistent with our experimental results. On the basis of 6o and 6q, it is expected to develop CYP1B1 inhibitors with stronger affinity, higher selectivity and better solubility.

Influence of Metal Coordination on the Gas-Phase Chemistry of the Positional Isomers of Fluorobenzoate Complexes.

The fragmentation behaviors of the o-, m-, and p-fluorobenzoate complexes of La3+, Ce3+, Fe3+, Cu2+, and UO22+ were investigated by electrospray ionization mass spectrometry, and the corresponding reaction mechanisms were explored by density functional theory (DFT) calculations. Fluoride transfer product LaIIIFCl3-/CeIIIFCl3- and decarboxylation product LaIIICl3(C6H4F)-/CeIIICl3(C6H4F)- were observed when the carboxylate precursors LaIIICl3(C6H4FCO2)-/CeIIICl3(C6H4FCO2)- were subjected to collision-induced dissociation. The variation in product ratios, which is not obvious in the meta and para cases, qualitatively follows the increasing overall energy barrier and reaction endothermicity of the two-step CO2/C6H4 elimination mechanism, and this aligns with the increase in U-F distance in the ortho, meta, and para decarboxylation product isomers. In contrast, the mass spectra of FeIIICl3(C6H4FCO2)-/CuIICl2(C6H4FCO2)- are dominated by the reduction product FeCl3-/CuCl2- regardless of the fluorobenzoate isomer. DFT/B3LYP calculations show that the two-step CO2/C6H4F elimination pathways are comparable in energy for all three positional isomers. It is energetically more favorable to give the reduction product than the fluoride transfer product, which is opposite to the lanthanum cases. Although the decarboxylation product was observed for all three UVIO2Cl2(C6H4FCO2)- isomers, the ortho isomer behaves more similarly to LaIIICl3(C6H4FCO2)-/CeIIICl3(C6H4FCO2)- as evidenced by the formation of UVIO2FCl2-, and the appearance of UVO2Cl2- in the cases of the meta and para isomers indicates the similarity with FeIIICl3(C6H4FCO2)-/CuIICl2(C6H4FCO2)-. The shorter U-F distance in UVIO2Cl2(o-C6H4F)- causes the decrease in the fluoride transfer barrier and thus makes this process more favorable over o-C6H4F radical loss to give UVO2Cl2-.

Gas-phase synthesis and structure of thorium benzyne complexes.

The thorium benzyne complex (η2-C6H4)ThCl3- was synthesized in the gas phase through consecutive decarboxylation and dehydrochlorination from the (C6H5CO2)ThCl4- precursor upon collision-induced dissociation. Theoretical calculations suggest that (η2-C6H4)ThCl3- exhibits a metallacyclopropene structure with two polarized Th-Cbenzyne σ bonds. This procedure can be generally extended to the synthesis of a wide range of gas-phase thorium benzyne complexes.

Discrimination and quantitation of halobenzoic acid positional isomers upon Th(IV) coordination by mass spectrometry.

A fast and reliable mass spectrometry-based method has been developed to discriminate the positional isomers of o-, m- and p-C6H4XCO2H (X = F, Cl and Br). This is based on the distinct fragmentation patterns of isomeric ThCl4(C6H4XCO2)- ions generated by electrospray ionization of the solutions with C6H4XCO2H isomers and ThCl4. Moreover, the composition of these positional isomers can be conveniently quantified without any pre-treatment according to the proportion of gas-phase fragmentation products.

Preparation of a bifunctional pyrazosulfuron-ethyl imprinted polymer with hydrophilic external layers by reversible addition-fragmentation chain transfer polymerization and its application in the sulfonylurea residue analysis.

A new bifunctional pyrazosulfuron-ethyl imprinted polymer was synthesized by the combination of molecular imprinting technology and living radical polymerization. In the synthesis, the pyrazosulfuron-ethyl imprinted polymer was obtained by the reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization followed by grafting poly(glyceryl monomethacrylate) (pGMMA) by the post-RAFT polymerization. In this research, we used polyethylene glycol (PEG) as the polymeric porogen in order to increase the porosity of the material which is a new porogen application in the precipitation polymerization. The imprinted polymer has selectivity for the template and ability of humic acids exclusion which has shown the merits of molecularly imprinted polymers and restricted access materials. An online solid-phase extraction/HPLC method for the analysis of three sulfonylurea residues in soil samples has been developed and validated. The recovery of 81-99% in the spiked levels of 40-200 µg kg(-1) was obtained and the limit of detection (LOD) and limit of quantification (LOQ) were less than 4.8 and 15.9 µg kg(-1) respectively. The results demonstrated that this bifunctional material can be used for the efficient pyrazosulfuron-ethyl extraction in the sulfonylurea residue analysis from environmental samples.