Article
Chemistry, Organic
Xiaozheng Dou, Bhargav A. Patel, Terin D'Amico, Chitra Subramanian, Eric Cousineau, Yi Yi, Mark Cohen, Brian S. J. Blagg
Summary: Hsp90 is a molecular chaperone involved in regulating protein folding and stability, and it plays a significant role in cancer development and progression. Inhibition of Hsp90 has emerged as a promising approach for cancer treatment, but currently available inhibitors have demonstrated toxic side effects. Cruentaren A, a natural product, shows potent anticancer activity by disrupting the interactions between Hsp90 alpha and F1FO ATP synthase without inducing the pro-survival heat shock response. However, the complex structure of Cruentaren A has hindered its development as an anticancer agent.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Xiaozheng Dou, Hui Guo, Terin D'Amico, Leah Abdallah, Chitra Subramanian, Bhargav A. Patel, Mark Cohen, John L. Rubinstein, Brian S. J. Blagg
Summary: Cruentaren A is a natural product with potent antiproliferative activity against cancer cell lines, and its structure when bound to ATP synthase has been determined using cryogenic electron microscopy (cryoEM), enabling the design of new inhibitors. One example is a trans-alkene isomer, which exhibits similar activity to Cruentaren A against three cancer cell lines, along with other analogues that also display potent inhibitory activity. These findings lay the groundwork for developing Cruentaren A derivatives as potential therapeutics for cancer treatment.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Multidisciplinary Sciences
David B. Konrad, Klaus-Peter Ruehmann, Hiroyasu Ando, Belinda E. Hetzler, Nina Strassner, Kendall N. Houk, Bryan S. Matsuura, Dirk Trauner
Summary: A stereoselective synthesis of TTX from a glucose derivative is presented, proceeding via 22 steps. This method provides ready access to biologically active derivatives.
Article
Chemistry, Organic
Gihan C. Dissanayake, Cornelius N. Ndi, Jana L. Markley, James B. Martinez, Paul R. Hanson
Summary: Two synthetic strategies involving phosphate tether-mediated one-pot sequential protocols were developed for the total synthesis of sanctolide A, a polyketide nonribosomal peptide macrolide, and the formal synthesis of its (2S)-epimer.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Giulio Fittolani, Theodore Tyrikos-Ergas, Ana Poveda, Yang Yu, Nishu Yadav, Peter H. Seeberger, Jesus Jimenez-Barbero, Martina Delbianco
Summary: This article introduces a synthetic glycan molecule that adopts a stable secondary structure not found in nature, called a glycan hairpin. The synthetic glycan is created by combining natural glycan motifs and utilizing unconventional hydrogen bonds and hydrophobic interactions. Nuclear magnetic resonance conformational analysis and long-range inter-residue nuclear Overhauser effects confirm the folded conformation of the synthetic glycan hairpin. The ability to control the 3D shape of glycans has the potential to provide more foldamer scaffolds with programmable properties and functions.
Article
Chemistry, Organic
Oscar Gayraud, Benjamin Laroche, Nicolas Casaretto, Bastien Nay
Summary: Aspochalasins are leucine-derived cytochalasins with a high level of biosynthetic oxidation, inspiring a two-phase strategy in total synthesis. A putative biomimetic tetracyclic intermediate was synthesized through an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, with the branched precursor obtained from a stereoselective Ireland-Claisen rearrangement. This also represents a formal synthesis of trichoderone A.
Article
Chemistry, Multidisciplinary
Yuan Jin, Kensuke Orihara, Fumiki Kawagishi, Tatsuya Toma, Tohru Fukuyama, Satoshi Yokoshima
Summary: The total synthesis of Haliclonin A was achieved through a series of reactions including Birch reduction/alkylation, ring-closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4-addition, leading to the formation of the desired compound.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Zorana Ferjancic, Andrej Kukuruzar, Filip Bihelovic
Summary: An enantioselective total synthesis of the monoterpenoid indole alkaloid (+)-alstonlarsine A (1) has been achieved, which possesses a unique pentacyclic skeleton and rare biological activity. The key step involves an efficient domino sequence, consisting of enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels-Alder cycloaddition for the construction of a 9-azatricyclo[4.3.1.0(3,8)]decane core. This strategy offers a new general entry into other tricyclic frameworks with fused indole ring and 6-, 7-, or 8-membered rings.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
David A. Evans, Jason J. Beiger, Jason D. Burch, Peter H. Fuller, Frank Glorius, Egmont Kattnig, David A. Thaisrivongs, William C. Trenkle, Joseph M. Young, Jing Zhang
Summary: The total syntheses of aflastatin A and its C3-C48 degradation fragment have been achieved, revealing a structural misassignment in the naturally derived degradation product. The revised absolute configurations of six stereogenic centers were also confirmed in this study.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Yuran Wang, Rong Zhao, Ming Yang
Summary: This study reports the first total synthesis method for mollanol A, which involves a 15-step synthesis process using a convergent strategy to construct its unique molecular structure.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Marko Nesic, David B. Ryffel, Jonathan Maturano, Michael Shevlin, Scott R. Pollack, Donald R. Gauthier Jr, Pablo Trigo-Mourin, Li-Kang Zhang, Danielle M. Schultz, Jamie M. McCabe Dunn, Louis-Charles Campeau, Niki R. Patel, David A. Petrone, David Sarlah
Summary: The collaborative total synthesis of darobactin A, a selective antibiotic against Gram-negative bacteria, has been achieved in a convergent manner using D-Garner's aldehyde and L-serine as starting materials. The synthesis involved 16 steps and three scalable routes were developed to synthesize non-canonical amino acids. The closure of the bismacrocycle was successfully achieved through sequential, halogen-selective Larock indole syntheses, with the cyclization order playing a crucial role in the formation of the desired atropisomer.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Venugopal Rao Challa, Daniel Kwon, Matthew Taron, Hope Fan, Baldip Kang, Darryl Wilson, F. P. Jake Haeckl, Sandra Keerthisinghe, Roger G. Linington, Robert Britton
Summary: The total synthesis of marine macrolide biselide A was achieved using enantiomerically enriched alpha-chloroaldehyde as the chiral building block. Strategies such as the macrocyclic Reformatsky reaction were utilized to construct the macrocycle in 18 steps. Biological testing revealed biselide A disrupts cell division through a mechanism related to microtubule cytoskeleton organization, suggesting potential for anticancer drug development in related marine macrolides.
Article
Multidisciplinary Sciences
Lingxiang Hou, Xueping Cui, Bo Guan, Shaozhi Wang, Ruian Li, Yunqi Liu, Daoben Zhu, Jian Zheng
Summary: In this study, a single-crystal 2D carbon material, monolayer quasi-hexagonal-phase fullerene (C-60), is prepared using an interlayer bonding cleavage strategy. This material exhibits high crystallinity, good thermodynamic stability, and has a moderate bandgap. The asymmetric lattice structure of monolayer polymeric C-60 gives it notable in-plane anisotropic properties. This 2D carbon material offers an interesting platform for potential applications in 2D electronic devices.
Article
Chemistry, Organic
Da-Ping Jin, Zhu-Peng Gao, Lin Liu, Shi-Qi Cao, Xue-Tao Xu, Xue-Wei Hou, Tian-Lu Zheng, Li-Ming Jiang, Dao-Yong Zhu, Shao-Hua Wang
Summary: The first total synthesis of (+/-)-furanether A, which demonstrates good antifeedant activity, was achieved in 13 linear steps. The key rigid tetracyclic skeleton containing a 1-methyl-8-oxabicyclo[3.2.1]octane moiety with two vicinal quaternary carbon centers was rapidly constructed in one step through a unique tandem C-H oxidation/oxa-[3,3] Cope rearrangement/aldol cyclization sequence.
Article
Chemistry, Organic
Yassin M. Elbatrawi, Taylor Gerrein, Avraz Anwar, Kamlesh M. Makwana, David Degen, Richard H. Ebright, Juan R. Del Valle
Summary: We have achieved the total synthesis and configurational assignment of pargamicin A, a highly oxidized nonribosomal peptide that effectively inhibits the growth of drug-resistant bacteria. Our synthetic strategy involves late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work facilitates the synthesis of pargamicin derivatives for structure-activity relationship studies and provides insights into accessing other piperazic acid-containing natural products with steric congestion.
Review
Biochemistry & Molecular Biology
Christopher M. Brackett, Brian S. J. Blagg
Summary: SUMOylation is an important post-translational modification involving the attachment of SUMO polypeptide to target proteins. Dysregulation of SUMOylation pathway is observed in cancer and neurological diseases, with upregulated SUMO enzymes correlated with prognosis and disease progression. Inhibitors of SUMOylation are being actively researched, including natural products, peptidomimetics, and synthetic derivatives identified via virtual screens.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Surgery
Chitra Subramanian, Rebecca Gorney, Ton Wang, Derek Ge, Nina Zhang, Ang Zuo, Brian S. J. Blagg, Mark S. Cohen
Summary: The study reveals that lenvatinib-resistant thyroid cancer cells exhibit increased dependency on glycolysis, which can be effectively treated by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids with KU757.
Review
Chemistry, Medicinal
Subhabrata Chaudhury, Bradley M. Keegan, Brian S. J. Blagg
Summary: Heat shock proteins (Hsps) act as molecular chaperones and are involved in the activation of the heat shock response (HSR) to counter abnormal physiological conditions and stress, potentially helping in conditions such as cancer and neurodegenerative diseases. Cellular stress results in the upregulation of Hsp70 transcription to protect cells, with Hsp90 being the primary regulator of the HSR and a potential target for therapeutic interventions in neuropathies.
MEDICINAL RESEARCH REVIEWS
(2021)
Article
Chemistry, Medicinal
Sanket J. Mishra, Weiya Liu, Kristin Beebe, Monimoy Banerjee, Caitlin N. Kent, Vitumbiko Munthali, John Koren, John A. Taylor, Leonard M. Neckers, Jeffrey Holzbeierlein, Brian S. J. Blagg
Summary: Hsp90 proteins play a crucial role in cancer progression, and inhibiting their activity may be beneficial for cancer treatment. Current Hsp90 inhibitors target all isoforms, potentially leading to adverse effects. Utilizing Hsp90 beta-selective inhibitors as a new approach for cancer therapy holds promise in reducing side effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Immunology
A. L. Heck, S. Mishra, T. Prenzel, L. Feulner, E. Achhammer, V Saerchen, B. S. J. Blagg, W. Schneider-Brachert, S. Schuetze, J. Fritsch
Summary: The study reveals that extrinsic cell death activation via TNF or TRAIL results in HSP90 beta degradation, promoting apoptosis induction.
Article
Chemistry, Medicinal
Dilip K. Tosh, Christopher M. Brackett, Young-Hwan Jung, Zhan-Guo Gao, Monimoy Banerjee, Brian S. J. Blagg, Kenneth A. Jacobson
Summary: The Grp94 isoform-selective inhibitor NECA has been identified as a promising molecule for the treatment of cancer and neurodegenerative diseases. Further studies are needed to develop inhibitors with the NECA scaffold that maintains selectivity towards Grp94.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Pharmacology & Pharmacy
Monimoy Banerjee, Ishita Hatial, Bradley M. Keegan, Brian S. J. Blagg
Summary: Hsp90 is a molecular chaperone essential for the maturation of diverse client proteins, some of which are cancer targets. Inhibiting Hsp90 activity offers potential for drug development in treating diseases such as cancer. Various assays and technologies are being used to find specific and potent Hsp90-targeting drugs.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Chemistry, Organic
Vishal C. Birar, Gene Zaid, Brian S. J. Blagg
Summary: The combination of herbal medicine and nutraceutical components can produce compounds with reduced toxicity for the treatment of human diseases such as cancer. Research has shown that specific combinations can exhibit activity against various human cancer cell lines.
TETRAHEDRON LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Yssa A. Rodriguez, Sukmanjit Kaur, Erika Nolte, Zhang Zheng, Brian S. J. Blagg, Rick T. Dobrowsky
Summary: Diabetic peripheral neuropathy (DPN) is linked to altered mitochondrial bioenergetics (mtBE), and KU-596 is a small molecule neurotherapeutic that can reverse DPN symptoms by improving sensory neuron mtBE and decreasing pro-oxidant protein Txnip. This study found that KU-596 therapy improved DPN, mtBE, and mitophagy in a manner dependent on Hsp70 but not Txnip. The results suggest that KU-596 may enhance mitochondrial tolerance to diabetic stress through a mechanism involving Hsp70 and Txnip.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Oncology
Jackee N. Sanchez, Chitra Subramanian, Monica Chanda, Gary Shanguan, Nina Zhang, Ton Wang, Barbara N. Timmermann, Brian S. J. Blagg, Mark S. Cohen
Summary: Melanoma is the most aggressive and fatal form of skin cancer, with a critical need for more durable therapeutic approaches to overcome drug resistance. Researchers have identified the role of Hsp90 protein in drug resistance pathways in melanoma, proposing a novel therapeutic strategy that can target multiple proteins and pathways simultaneously.
Review
Pharmacology & Pharmacy
Michael A. Serwetnyk, Brian S. J. Blagg
Summary: Hsp90 is a crucial molecular chaperone with potential as a target for cancer therapy. In addition to known inhibitory mechanisms, alternative approaches for Hsp90 inhibition are being explored.
ACTA PHARMACEUTICA SINICA B
(2021)
Meeting Abstract
Biochemistry & Molecular Biology
Kerry Chou, Christopher Brackett, Sanket Mishra, Brian Blagg, John Streicher
Article
Oncology
Jia Zhou, Camille Gelot, Constantia Pantelidou, Adam Li, Hatice Yucel, Rachel E. Davis, Anniina Farkkila, Bose Kochupurakkal, Aleem Syed, Geoffrey Shapiro, John A. Tainer, Brian S. J. Blagg, Raphael Ceccaldi, Alan D. D'Andrea
Summary: The antibiotic novobiocin has been identified as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors, including those with acquired PARP inhibitor resistance. This study suggests that novobiocin may be useful alone or in combination with PARP inhibitors for treating HR-deficient tumors.
Meeting Abstract
Oncology
C. Subramanian, J. Zhu, D. Lubman, B. S. Blagg, M. S. Cohen
ANNALS OF SURGICAL ONCOLOGY
(2021)
Meeting Abstract
Oncology
M. K. Chanda, C. Subramanian, J. Sanchez, B. S. Blagg, M. S. Cohen, K. Spielbauer
ANNALS OF SURGICAL ONCOLOGY
(2021)
