Article
Oncology
Victor M. Matias-Barrios, Mariia Radaeva, Yi Song, Zaccary Alperstein, Ahn R. Lee, Veronika Schmitt, Joseph Lee, Fuqiang Ban, Ning Xie, Jianfei Qi, Nada Lallous, Martin E. Gleave, Artem Cherkasov, Xuesen Dong
Summary: TOP2 catalytic inhibitors effectively suppress cancer cell proliferation with low cytotoxicity. The newly discovered compound T60 shows promise as a potential anticancer drug.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Victor M. Matias-Barrios, Mariia Radaeva, Chia-Hao Ho, Joseph Lee, Hans Adomat, Nada Lallous, Artem Cherkasov, Xuesen Dong
Summary: DNA topoisomerase II (TOP2) is a drug target for many types of cancers. Clinically used TOP2 inhibitors can have serious side effects, but new inhibitors with different mechanisms of action are being developed to effectively control tumor growth. The compound T638, a catalytic TOP2 inhibitor, shows promising potential as an anticancer drug candidate with limited genotoxicity to cells.
Article
Biochemistry & Molecular Biology
Kyung-Hwa Jeon, Seojeong Park, Hae Jin Jang, Soo-Yeon Hwang, Aarajana Shrestha, Eung-Seok Lee, Youngjoo Kwon
Summary: The study revealed that AK-I-190, a novel topoisomerase II inhibitor, exerts potent inhibitory activity by intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in less DNA toxicity compared to etoposide. AK-I-190 induces G1 arrest and effectively inhibits cell proliferation and colony formation in an androgen receptor-negative CRPC cell line, indicating the potential clinical relevance of topoisomerase II catalytic inhibitors in treating this type of prostate cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Jin-Hee Kwon, Na-Gyeong Lee, A-Ram Kang, In-Ho Ahn, In-Young Choi, Jie-Young Song, Sang-Gu Hwang, Hong-Duck Um, Jong-Ryoo Choi, Joon Kim, Jong Kuk Park
Summary: The objective of this study was to investigate the potential anticancer and radiosensitizing effects of JNC-1043 in colorectal cancer cells. The results demonstrated that JNC-1043 inhibited cell proliferation, enhanced cell death and apoptosis, and increased mitochondrial ROS production when combined with gamma-ionizing radiation. These findings suggest that JNC-1043 acts as a radiosensitizer and exerts its anticancer effects by promoting apoptosis through mitochondrial ROS.
Review
Pharmacology & Pharmacy
Emma Baglini, Silvia Salerno, Elisabetta Barresi, Marco Robello, Federico Settimo, Sabrina Taliani, Anna Maria Marini
Summary: DNA topoisomerases are crucial enzymes involved in DNA topology regulation, with inhibitors targeting TopoI and TopoII showing broad-spectrum antitumor activities and potential to reduce drug resistance and side effects in cancer treatment. Targeting both enzymes simultaneously could provide more efficient and safe drugs for clinical usage.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Chemistry, Medicinal
Guangsen Xu, Zhiying Li, Yanjiao Ding, Yuemao Shen
Summary: Fifty-eight pinosylvin derivatives were designed and synthesized as topoisomerase II (TopoII) inhibitors, with the most potent compound F2 showing high inhibitory efficacy against TopoII and strong antitumor activities against multiple human cancer cell lines. F2 also exhibited less cytotoxicity against normal cells compared to the chemotherapeutic agent VP-16.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Potlapati Varakumar, Kalirajan Rajagopal, Baliwada Aparna, Kannan Raman, Gowramma Byran, Clara Mariana Goncalves Lima, Salma Rashid, Mohammed H. Nafady, Talha Bin Emran, Slawomir Wybraniec
Summary: This review provides a summary of the recent advancements in the chemistry of acridines as anti-cancer agents, including new structural and biologically active attributes. Acridine derivatives are extensively studied as potential anti-cancer drugs. Despite their high cytotoxic activity, the clinical application of acridines is limited or even excluded due to side effects.
Article
Biochemistry & Molecular Biology
Caroline Molinaro, Nathalie Wambang, Sylvain Pellegrini, Natacha Henry, Marc F. Lensink, Emmanuelle Germain, Till Bousquet, Jerome de Ruyck, Katia Cailliau, Lydie Pelinski, Alain Martoriati
Summary: Topoisomerase inhibitors, such as the copper-derived indenoisoquinoline complex WN198 described in this study, have potential as effective treatments for cancer. The compound demonstrated cytotoxic effects on multiple cancer cell lines, particularly the triple-negative MDA-MB-231 breast cancer cell line, while not affecting non-tumorigenic cells. In addition, the compound exhibited DNA interaction and topoisomerase I activity, suggesting its potential as a DNA-damaging treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Microbiology
Iwona Gabriel, Kamila Rzad, Ewa Paluszkiewicz, Katarzyna Kozlowska-Tylingo
Summary: Increased importance is being placed on issues caused by fungal pathogens, with current methods for prevention being insufficient. Capridine beta shows potential as a novel antifungal drug, with its activity depending on the type of strains analyzed and its biotransformation in cells.
Article
Biochemistry & Molecular Biology
Kyung-Hwa Jeon, Aarajana Shrestha, Hae Jin Jang, Jeong-Ahn Kim, Naeun Sheen, Minjung Seo, Eung-Seok Lee, Youngjoo Kwon
Summary: Topoisomerase II alpha has been a significant anti-cancer target due to its functional necessity in highly proliferative cancer cells. Topoisomerase II poisons, as drugs targeting IIa, are commonly used in clinical settings but can cause DNA toxicity, necessitating the development of catalytic inhibitors through alternative mechanisms. AK-I-191, as a catalytic inhibitor, exhibits potent inhibitory activity and synergistic effects with tamoxifen in anti-proliferative activity.
BIOMOLECULES & THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Lini Huo, Xiaochen Liu, Yogini Jaiswal, Hao Xu, Rui Chen, Rumei Lu, Yaqin Nong, Leonard Williams, Yan Liang, Zhiruo Jia
Summary: We designed and synthesized a series of novel acridine-triazole and acridine-thiadiazole derivatives. These compounds showed high levels of antitumor activity against gastric cancer cells and bladder cancer cells, while exhibiting low toxicity to normal liver cells. Moreover, their pharmacological mechanisms and effects on cell cycle and apoptosis were evaluated. Furthermore, these compounds demonstrated low cytotoxicity to zebrafish but strong inhibition of the formation of zebrafish sub-intestinal veins, suggesting potential clinical applications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Daria Rozycka, Aleksandra Kowalczyk, Marta Denel-Bobrowska, Olga Kuzmycz, Magdalena Gapinska, Pawel Staczek, Agnieszka B. Olejniczak
Summary: Synthesis of carborane-modified acridine analogs showed their DNA-binding ability and potential anticancer activities. Compound 30 demonstrated strong interaction with ct-DNA, while compound 29 changed the conformation of ct-DNA. Compound 30 exhibited cytotoxicity, inhibited cell proliferation, arrested the cell cycle, and induced reactive oxygen species production in the HeLa cancer cell line.
Article
Chemistry, Medicinal
Kamila Rzad, Ewa Paluszkiewicz, Iwona Gabriel
Summary: The study synthesized 12 novel antifungal compounds and found that some of them were effective in inhibiting Candida albicans with different mechanisms compared to other drugs. These newly synthesized compounds also exhibited anti-biofilm activity, with IE10 showing the best performance, and only IE6 showed antifungal activity against fluconazole-resistant C. albicans strains.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Soo-Yeon Hwang, Aarajana Shrestha, Seojeong Park, Ganesh Bist, Surendra Kunwar, Tara Man Kadayat, Haejin Jang, Minjung Seo, Naeun Sheen, Seojeong Kim, Kyung-Hwa Jeon, Eung-Seok Lee, Youngjoo Kwon
Summary: A novel series of halogen-containing indenopyridin-5-one compounds were designed and synthesized, with some showing strong inhibition of topoisomerase I/II alpha and potential anticancer activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
Seungmin Han, Kwang Suk Lim, Brody J. Blackburn, Jina Yun, Charles W. Putnam, David A. Bull, Young-Wook Won
Summary: DNA topoisomerases are crucial enzymes for maintaining DNA stability, with topoisomerase inhibitors being utilized as anti-cancer drugs. Among them, camptothecin and its derivatives have shown promise due to their ability to trap TOP1 cleavage complexes. The development of TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) has led to improved therapeutic efficacy, with potential for further enhancement through combinatorial strategies.
Article
Chemistry, Medicinal
Peter Larson, Tamara A. Kucaba, Zhengming Xiong, Michael Olin, Thomas S. Griffith, David M. Ferguson
ACS MEDICINAL CHEMISTRY LETTERS
(2017)
Article
Engineering, Biomedical
Hyunjoon Kim, Lin Niu, Peter Larson, Tamara A. Kucaba, Katherine A. Murphy, Britnie R. James, David M. Ferguson, Thomas S. Griffith, Jayanth Panyam
Article
Chemistry, Medicinal
Matthew R. Bockman, Curtis A. Engelhart, Surendra Dawadi, Peter Larson, Divya Tiwari, David M. Ferguson, Dirk Schnappinger, Courtney C. Aldrich
ACS INFECTIOUS DISEASES
(2018)
Article
Medicine, Research & Experimental
Hyunjoon Kim, Vidhi Khanna, Tamara A. Kucaba, Wenqiu Zhang, David M. Ferguson, Thomas S. Griffith, Jayanth Panyam
MOLECULAR PHARMACEUTICS
(2019)
Article
Chemistry, Medicinal
Matthew R. Bockman, Curtis A. Engelhart, Julia D. Cramer, Michael D. Howe, Neeraj K. Mishra, Matthew Zimmerman, Peter Larson, Nadine Alvarez-Cabrera, Sae Woong Park, Helena I. M. Boshoff, James M. Bean, Victor G. Young, David M. Ferguson, Veronique Dartois, Joseph T. Jarrett, Dirk Schnappinger, Courtney C. Aldrich
ACS INFECTIOUS DISEASES
(2019)
Article
Chemistry, Medicinal
Xu Wang, Yuna Zeng, Li Sheng, Peter Larson, Xue Liu, Xiaowen Zou, Shufang Wang, Kaijing Guo, Chen Ma, Gang Zhang, Huaqing Cui, David M. Ferguson, Yan Li, Jingren Zhang, Courtney C. Aldrich
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Medicine, Research & Experimental
Hyunjoon Kim, Vidhi Khanna, Tamara A. Kucaba, Wenqiu Zhang, Drishti Sehgal, David M. Ferguson, Thomas S. Griffith, Jayanth Panyam
MOLECULAR PHARMACEUTICS
(2020)
Editorial Material
Chemistry, Medicinal
Zhengqiang Wang, David Ferguson
MEDICINAL CHEMISTRY RESEARCH
(2021)
Article
Chemistry, Medicinal
Diego E. Escalante, David M. Ferguson
Summary: This study elucidates the structure and pharmacological characteristics of TMPRSS2, demonstrating its active site and catalytic function through molecular dynamics simulations. It reveals the potential binding mode and mechanism of inhibitors, providing insights for the design of therapeutics targeting TMPRSS2.
MEDICINAL CHEMISTRY RESEARCH
(2021)
Article
Multidisciplinary Sciences
Vidhi Khanna, Hyunjoon Kim, Wenqiu Zhang, Peter Larson, Manan Shah, Thomas S. Griffith, David Ferguson, Jayanth Panyam
Summary: New small molecule TLR7/8 agonists were found to induce significantly higher cytokines and activate NK cells, enhancing ADCC and anti-cancer efficacy of monoclonal antibodies. These agonists also stimulated CD8 T cells, suggesting an early adaptive immune response.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Organic
Peter G. Larson, David M. Ferguson
Summary: The study presents a synthetic route to obtain substituted thiazoloquinolines with electron-withdrawing groups at the C7 position, addressing limitations in current strategies for diverse substitutions at the C6-C9 positions of thiazolo- and oxazoloquinolines.
Article
Chemistry, Medicinal
Mu Yang, Peter G. Larson, Lincoln Brown, John R. Schultz, Tamara A. Kucaba, Thomas S. Griffith, David M. Ferguson
Summary: This study investigates the effect of isomeric substitutions to the C2-butyl group of imidazoquinoline agonists on Toll-like receptors (TLR) 7 and 8. The results show that the conformations of the dimeric receptor complex are highly sensitive to steric perturbations, indicating the importance of the ligand binding pocket in regulating the receptor signal. This finding has significant implications for the design of immunomodulatory agents.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Diego E. Escalante, Courtney C. Aldrich, David M. Ferguson
Summary: In this study, the molecular mechanics force field used for modeling the energetic and conformational interconversions of highly substituted furanose rings was improved. The parameters were optimized and validated by comparing with experimental results.
Article
Biochemistry & Molecular Biology
Nagamani Vunnam, Mu Yang, Chih Hung Lo, Carolyn Paulson, William D. Fiers, Evan Huber, MaryJane Been, David M. Ferguson, Jonathan N. Sachs
Summary: In this study, analogues of zafirlukast were synthesized and tested for their efficacy and potency in TNFR1 signaling. Three analogues were identified with significantly improved efficacy and potency, each inducing a conformational change in the receptor. However, despite these improvements, the best candidate only achieved 63% inhibition of NF-kappa B, leaving room for further improvements. Interestingly, the analogues also bound to TNFR2 but did not inhibit its function or cause any conformational changes upon binding.
ACS BIO & MED CHEM AU
(2023)
Article
Chemistry, Multidisciplinary
Hyunjoon Kim, Drishti Sehgal, Tamara A. Kucaba, David M. Ferguson, Thomas S. Griffith, Jayanth Panyam