Article
Chemistry, Medicinal
Alessandra Ammazzalorso, Marialucia Gallorini, Marialuigia Fantacuzzi, Nicola Gambacorta, Barbara De Filippis, Letizia Giampietro, Cristina Maccallini, Orazio Nicolotti, Amelia Cataldi, Rosa Amoroso
Summary: Novel aromatase inhibitors based on triazole and imidazole-based carbamate derivatives were designed and synthesized, with compounds 13a and 15c showing dose-dependent inhibition of cell viability on the human breast cancer cell line MCF7. Docking simulations were also carried out to elucidate the binding modes of these active compounds to target human aromatase at a molecular level.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Lilan Xin, Jian Min, Hebing Hu, Yuanyuan Li, Chuanqian Du, Baohua Xie, Yan Cheng, Xiaofei Deng, Xiangping Deng, Kang Shen, Jian Huang, Chun -Chi Chen, Rey-Ting Guo, Chune Dong, Hai -Bing Zhou
Summary: In this study, a novel class of dual-targeting selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. These compounds showed excellent ERa degradation activity, ARO inhibitory activity, and antiproliferative activity against drug-resistant breast cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biology
Vivek K. Vyas, Tanvi Shukla, Kartik Tulsian, Manmohan Sharma, Shivani Patel
Summary: This study presents structure-guided computational strategies for the design of novel quinolizin-4-ones as PfDHODH inhibitors. The virtual screening and docking studies suggest that quinolizin-4-ones have potential anti-malarial activity.
COMPUTATIONAL BIOLOGY AND CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Chamandi S. Dampalla, Athri D. Rathnayake, Anushka C. Galasiti Kankanamalage, Yunjeong Kim, Krishani Dinali Perera, Harry Nhat Nguyen, Matthew J. Miller, Trent K. Madden, Hunter R. Picard, Hayden A. Thurman, Maithri M. Kashipathy, Lijun Liu, Kevin P. Battaile, Scott Lovell, Kyeong-Ok Chang, William C. Groutas
Summary: The 3C-like protease (3CLpro) of SARS-CoV-2 has been validated as an effective target for developing therapeutics. Highly potent inhibitors have been successfully designed based on structure-guided design, and their mechanism of action has been established using high-resolution cocrystal structures.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Ashima Dhiman, Rupam Sharma, Rajesh K. Singh
Summary: Cancer, the second leading cause of death after heart disease, is characterized by the uncontrolled growth of cells. Targeting specific genes and proteins involved in the growth and survival of cancer cells has become a top priority in global research. Indole moiety, a combination of aromatic-heterocyclic compounds, has emerged as a promising scaffold for the development of anticancer drugs due to its bioavailability, unique chemical properties, and significant pharmacological behaviors. Recent advances in the medicinal chemistry of indole derivatives, including the synthesis of potential anticancer compounds and their mechanism of action, are discussed in this review.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Medicinal
Mark Montgomery, Stefano Rendine, Christoph T. Zimmer, Jan Elias, Jurgen Schaetzer, Thomas Pitterna, Fides Benfatti, Marisa Skaljac, Aurelien Bigot
Summary: The development of novel and safe insecticides is crucial for protecting crops and animal and human health. In this study, the crystal structures of several insecticides were revealed, leading to the discovery of new pharmacophores with a related mode of action.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Derya Osmaniye, Sennur Gorgulu, Begum Nurpelin Saglik, Serkan Levent, Yusuf Ozkay, Zafer Asim Kaplancikli
Summary: The study aimed at developing new aromatase inhibitors, some of which showed high anticancer activity and induced apoptosis in lung and breast cancer cell lines. Compound 2g and 2l were found to possess significant anticancer activity.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Chiara Brullo, Federica Rapetti, Sara Abbate, Tommaso Prosdocimi, Archimede Torretta, Marta Semrau, Matteo Massa, Silvana Alfei, Paola Storici, Emilio Parisini, Olga Bruno
Summary: Memory and cognitive functions rely on the levels of cyclic adenosine monophosphate (cAMP) in the brain, which are regulated by the phosphodiesterase 4 (PDE4) enzyme family. Certain PDE4 inhibitors can increase hippocampal cAMP levels, leading to cognitive benefits. Studies have shown that ligands can adopt different conformations, affecting their interaction with the enzyme.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, General & Internal
Milana A. Bergamino, Elena Lopez-Knowles, Gabriele Morani, Holly Tovey, Lucy Kilburn, Eugene F. Schuster, Anastasia Alataki, Margaret Hills, Hui Xiao, Chris Holcombe, Anthony Skene, John F. Robertson, Ian E. Smith, Judith M. Bliss, Mitch Dowsett, Maggie C. U. Cheang
Summary: This study aimed to identify biomarkers for the response of ER+/HER2+ breast cancers to AI treatment. The results showed that HER2-E is a standardized biomarker associated with poor response to AI and worse prognosis in ER+/HER2+ breast cancers. HRD, TP53 mutational score, and immune-tumor tolerance are predictive biomarkers for poor response to AI. Additionally, new molecular subtypes identify non-HER2-E tumors that do not respond to AI and have an increased risk of relapse.
Article
Chemistry, Medicinal
Yuqin Lei, Qi An, Xiao-Fei Shen, Min Sui, Chungen Li, Da Jia, Youfu Luo, Qingxiang Sun
Summary: The research team successfully designed a noncovalent CRM1 inhibitor with high affinity for human and yeast CRM1 through crystal structure studies, showing superior properties compared to covalent inhibitors. This discovery opens up new avenues for the development of more effective, less toxic, and broad-spectrum anticancer/antiviral therapies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Fernanda M. F. Roleira, Saul C. Costa, Ana R. Gomes, Carla L. Varela, Cristina Amaral, Tiago Augusto, Georgina Correia-da-Silva, Isabella Romeo, Giosue Costa, Stefano Alcaro, Natercia Teixeira, Elisiario J. Tavares-da-Silva
Summary: New steroidal aromatase inhibitors (AIs) were synthesized and tested. Carbonyl group at C-11 position and C-ring epoxides were found to be more effective in aromatase inhibition. Compound 7 exhibited the strongest AI activity with an IC50 of 0.011 μM, outperforming the clinically used AI Exemestane with an IC50 of 0.050 μM. A-ring epoxides were found to be less potent than A-ring olefins. 713-methyl substitution was shown to be more effective than 7 alpha-methyl substitution in aromatase inhibition.
BIOORGANIC CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Ankita Sood, Damanpreet Kaur Lang, Rajwinder Kaur, Balraj Saini, Sandeep Arora
Summary: Treatment for breast cancer remains challenging, with aromatase inhibitors showing significantly improved efficacy and safety compared to other drugs.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2021)
Article
Neurosciences
Alev Selek, Zehra Seda Unal Halbutogullari, Cigdem Inci Aydemir, Berrin Cetinarslan, Zeynep Canturk, Ilhan Tarkun, Gulay Erman, Cansu Subasi, Karaoz Erdal
Summary: This study investigates the potential of using an aromatase inhibitor as a substitute for testosterone in treating prolactinomas. The findings reveal that the aromatase inhibitor can inhibit cell proliferation and induce apoptosis in prolactinoma cells, as well as reduce prolactin and estrogen levels.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Chemistry, Medicinal
Amit Kumar Jana, Jyotsana Singh, Asha Ganesher, Amit Kumar, Arpita Banerjee, Deepak Kumar, Sarvesh Kumar Verma, Ashok Kumar Sharma, Rabi Sankar Bhatta, Rituraj Konwar, Gautam Panda
Summary: A new chemical entity, benzoxazine, was designed for improving anti-breast cancer activity. Compound 13d, as a lead compound, induced apoptosis, cell cycle arrest, and loss of mitochondrial membrane potential in breast cancer cells. In a rat syngenic mammary tumor model, both 13d and 13d-f showed significant tumor regression without causing any mortality.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Medicine, General & Internal
Amit Akirov, Yaron Rudman
Summary: This study systematically reviewed the role of aromatase inhibitors in the treatment of male prolactinomas with dopamine-agonist-resistant or persistent hypogonadism. The results showed that aromatase inhibitors can reduce estrogen levels, improve sensitivity to dopamine agonists, and control prolactin levels, leading to the shrinking of tumors.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Ryan C. Cammarota, Wenbin Liu, John Bacsa, Huw M. L. Davies, Matthew S. Sigman
Summary: Leveraging congested catalyst scaffolds is a key strategy for altering substrate site-selectivity in C-H functionalization reactions. In this study, a new set of descriptors (SMART) was developed to quantify reactive site spatial constraints for a library of dirhodium catalysts and predict site-selectivity for C-H functionalization reactions. The study also developed global site-selectivity models to assess the roles of steric congestion and dirhodium-carbene electrophilicity in controlling the site of C-H functionalization.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Organic
Robert W. Kubiak, William F. Tracy, Joshua S. Alford, Huw M. L. Davies
Summary: This paper describes a rhodium-catalyzed enantioselective synthesis of 1-phenoxy-cyclopropane-1-carbaldehydes by intermolecular cyclopropanation of terminal alkenes followed by imine hydrolysis. The reaction proceeds via rhodium-stabilized donor/acceptor carbene intermediates, and the study demonstrates compatibility of a heteroatom donor group with enantioselective transformation.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Yannick T. Boni, Ryan C. Cammarota, Kuangbiao Liao, Matthew S. Sigman, Huw M. L. Davies
Summary: In this work, C-H functionalization of silyl ethers via carbene-induced C-H insertion has been achieved, providing an efficient synthetic disconnection strategy. The use of different catalyst preferences has enabled site- and stereoselective functionalization at different positions relative to the siloxy group. Additionally, a machine learning model has been developed to predict the major product, aiding in the application of these methods to new substrates.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Physical
Jack C. Sharland, David Dunstan, Dyuti Majumdar, Jinhai Gao, Kian Tan, Hasnain A. Malik, Huw M. L. Davies
Summary: In the presence of HFIP, nucleophilic and reactive reagents are prevented from interacting with a rhodium carbene, allowing for efficient asymmetric cyclopropanation with high yield and stereoselectivity on a variety of compounds. A high-throughput screen was conducted to expand the scope of the reaction and develop complementary catalytic systems, leading to the enantioselective functionalization of complex molecules including API and natural products.
Article
Chemistry, Physical
Zhi Ren, Djamaladdin G. Musaev, Huw M. L. Davies
Summary: Computational studies on the dirhodium(tetracarboxylate)-catalyzed C-H functionalization reveal that the enantioselectivity and site-selectivity of this reaction are controlled by the ratio of conformers of both the diazo compound and the dirhodium carbene intermediates and two distinct steps of the reaction. The findings provide important insights into the mechanism and factors influencing the selectivity of this catalytic reaction.
Article
Chemistry, Organic
Christian J. Bettencourt, Tanja Krainz, Sharon Chow, Brendan T. Parr, William F. Tracy, Paul V. Bernhardt, Huw M. L. Davies, Craig M. Williams
Summary: The rhodium(II)-catalyzed reaction of a model alkenyl donor/ acceptor N-sulfonyltriazole with a wide selection of furans has been reported. A range of structurally diverse carbocyclic and ring-opened products were obtained, in good to excellent yields, via selective cyclopropanation or zwitterionic rearrangement pathways, depending on the structural and electronic features of the furan substrate.
Article
Chemistry, Organic
Yannick T. Boni, Janakiram Vaitla, Huw M. L. Davies
Summary: Rhodium(II) catalyst-controlled site- and stereo-selective carbene insertion into the allylic C(sp3)-H bond of allyl boronates is achieved. The chiral catalyst Rh2(S-TPPTTL)4 exhibits high fidelity and asymmetric induction, enabling diastereoselective and enantioselective C-C bond formation without interference from the allyl boronate functionality. The resulting functionalized allyl boronates are amenable to stereo-selective allylations, leading to products with control of stereochemistry at four contiguous stereogenic centers.
Article
Chemistry, Physical
Korkit Korvorapun, Yannick T. Boni, Thomas C. Maier, Armin Bauer, Thomas Licher, John E. Macor, Volker Derdau, Huw M. L. Davies
Summary: Rhodium-catalyzed C-H insertion by donor/acceptor carbenes is a useful transformation in organic synthesis, but the site-selectivity of the C-H transformation on the target molecule is often a major issue. Chiral rhodium carbene intermediates can achieve site-selective C-H functionalizations of challenging substrates such as N-aryl and N-heteroaryl piperidines, leading to the formation of highly stereoselective C-2 products. Additionally, N-aryl morpholines and piperazines can selectively react at the alpha position to the N-aryl group.
Article
Chemistry, Organic
Farzaneh Saeedifard, Yasir Naeem, Yannick T. Boni, Yi-Chien Chang, Junxiang Zhang, Yadong Zhang, Bernard Kippelen, Stephen Barlow, Huw M. L. Davies, Seth R. Marder
Summary: Hole-transport materials based on triarylamine derivatives have critical applications in organic electronics. This study demonstrates a method using Rh-carbenoid chemistry to incorporate carboxylic esters and norbornene functional groups into triarylamine materials. The resulting materials exhibit similar properties to those synthesized by conventional means and offer the potential for diverse hole-transport materials with different functional groups.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Sebastian Fischer, Terrence-Thang H. Nguyen, Andreas Ratzenboeck, Huw M. L. Davies, Oliver Reiser
Summary: A stereoselective, solvent- and metal-free method for endocyclic C-C bond cleavage of monocyclopropanated cyclopentadienes mediated by strong acids has been developed. It leads to the formation of highly functionalized six-membered carbocycles with high stereocontrol. The critical step involves the formation of a cyclopropyl carbocation that undergoes endocyclic ring opening through an SN2'-type attack of various nucleophiles. Subsequent synthetic transformations demonstrate the versatility of the resulting cyclohexenes for the synthesis of compounds with nonconventional substitution patterns.
Article
Chemistry, Organic
Ziyi Chen, Qinyan Cai, Yannick T. Boni, Wenbin Liu, Jiantao Fu, Huw M. L. Davies
Summary: The rhodium-catalyzed enantioselective C-H functionalization of unactivated C-H bonds by donor/acceptor carbene-induced C-H insertion can be extended to substrates containing nitrogen functionality. The rhodium-stabilized donor/acceptor carbenes are generated by rhodium-catalyzed decomposition of aryldiazoacetates. The phthalimido group is the optimal nitrogen protecting group. C-H functionalization at the most sterically accessible site can be achieved using Rh-2(S-2-Cl-5-BrTPCP)(4) as catalyst, while Rh-2(S-TPPTTL)(4) is the most effective catalyst for functionalization at tertiary C-H bonds and for the desymmetrization of N-phthalimidocyclohexane.
Article
Chemistry, Organic
Maizie Lee, Huw M. L. Davies
Summary: The rhodium-catalyzed C-H functionalization of cyclohexadiene derivatives with diaryldiazomethanes, followed by oxidation with DDQ, allows for the synthesis of triarylmethanes. Two chiral dirhodium tetracarboxylates, Rh-2(S-PTAD)(4) and Rh-2(S-TPPTTL)(4), were identified as the optimal chiral catalysts for this transformation. This method demonstrates the ability of diaryldiazomethanes to perform intermolecular C-H insertion with high enantioselectivity and good yields. The broad substrate scope includes various aryl and heteroaryl substituents, including benzofuran and pyridine heterocycles.
Correction
Chemistry, Organic
Sebastian Fischer, Terrence-Thang H. Nguyen, Andreas Ratzenboeck, Huw M. L. Davies, Oliver Reiser
Article
Chemistry, Inorganic & Nuclear
Joshua K. Sailer, Jack C. Sharland, John Bacsa, Caleb F. Harris, John F. Berry, Djamaladdin G. Musaev, Huw M. L. Davies
Summary: A series of chiral bowl-shaped diruthenium(II,III) tetracarboxylate catalysts were prepared for asymmetric cyclopropanation reactions. These diruthenium catalysts self-assembled to form C(4)-symmetric bowl-shaped structures, similar to their dirhodium counterparts. The best catalyst, Ru-2(S-TPPTTL)(4)& BULL;BArF, achieved up to 94% ee in the cyclopropanation of various substrates. In contrast, the copper and cobalt congeners produced catalysts with little to no asymmetric induction. Computational studies revealed that the carbene complexes of the dicopper and dicobalt systems were prone to losing carboxylate ligands, which are essential for the bowl-shaped structure critical for asymmetric induction.
Article
Chemistry, Organic
Farzaneh Saeedifard, Yasir Naeem, Yannick T. Boni, Yi-Chien Chang, Junxiang Zhang, Yadong Zhang, Bernard Kippelen, Stephen Barlow, Huw M. L. Davies, Seth R. Marder
Summary: Hole-transport materials (HTMs) based on triarylamine derivatives are important in organic electronic applications. This study presents a method to incorporate carboxylic esters and norbornene functional groups into sp2 C-H bonds of triarylamine materials using Rh-carbenoid chemistry. The resulting materials exhibit similar properties to those synthesized by conventional means and offer a straightforward approach to diverse HTMs with different functional groups.
JOURNAL OF ORGANIC CHEMISTRY
(2023)