Design, Synthesis, and Biological Investigation of Epothilone B Analogues Featuring Lactone, Lactam, and Carbocyclic Macrocycles, Epoxide, Aziridine, and 1,1-Difluorocyclopropane and Other Fluorine Residues

2020 ◽  
Vol 85 (5) ◽  
pp. 2865-2917 ◽  
Author(s):  
K. C. Nicolaou ◽  
Yogesh G. Shelke ◽  
Balu D. Dherange ◽  
Aaron Kempema ◽  
Baiwei Lin ◽  
...  
Keyword(s):  
Biological Investigation ◽  
Design Synthesis ◽  
Epothilone B

Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs

2021 ◽  
Vol 86 (3) ◽  
pp. 2499-2521
Author(s):  
K. C. Nicolaou ◽  
Santhosh Reddy Rekula ◽  
S. Mothish Kumar ◽  
Ananda Rao Podilapu ◽  
Ryan P. Matuszak ◽  
...  
Keyword(s):  
Biological Investigation ◽  
Structural Motifs ◽  
Design Synthesis

Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues

2003 ◽  
Vol 42 (30) ◽  
pp. 3515-3520 ◽  
Author(s):  
K. C. Nicolaou ◽  
Pradip K. Sasmal ◽  
Gerasimos Rassias ◽  
Mali Venkat Reddy ◽  
Karl-Heinz Altmann ◽  
...  
Keyword(s):  
Biological Properties ◽  
Design Synthesis ◽  
Epothilone B

Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies

2017 ◽  
Vol 27 (17) ◽  
pp. 3974-3979 ◽  
Author(s):  
Harbinder Singh ◽  
Jatinder V. Singh ◽  
Manish K. Gupta ◽  
Ajit K. Saxena ◽  
Sahil Sharma ◽  
...  
Keyword(s):  
Docking Studies ◽  
Biological Investigation ◽  
Design Synthesis ◽  
Molecular Hybrids

Design, synthesis and biological investigation of certain pyrazole-3-carboxylic acid derivatives as novel carriers for nitric oxide

2009 ◽  
Vol 17 (11) ◽  
pp. 3829-3837 ◽  
Author(s):  
El-Shimaa M.N. Abdel-Hafez ◽  
Gamal El-Din A.A. Abuo-Rahma ◽  
Mohamed Abdel-Aziz ◽  
Mohamed F. Radwan ◽  
Hassan H. Farag
Keyword(s):  
Nitric Oxide ◽  
Carboxylic Acid ◽  
Biological Investigation ◽  
Design Synthesis

scholarly journals Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3496 ◽  
Author(s):  
Irina V. Il’ina ◽  
Nadezhda S. Dyrkheeva ◽  
Alexandra L. Zakharenko ◽  
Alexander Yu. Sidorenko ◽  
Nikolay S. Li-Zhulanov ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Gene Knockout ◽  
Biological Investigation ◽  
Cytotoxic Effects ◽  
Design Synthesis ◽  
Structural Types ◽  
Promising Target ◽  
Ic50 Value ◽  
Cytotoxic Compounds ◽  
Hek293ft Cell

Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 −/− cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

Streamlined Symmetrical Total Synthesis of Disorazole B1 and Design, Synthesis, and Biological Investigation of Disorazole Analogues

2020 ◽  
Vol 142 (36) ◽  
pp. 15476-15487
Author(s):  
K. C. Nicolaou ◽  
Johannes Krieger ◽  
Ganesh M. Murhade ◽  
Parthasarathi Subramanian ◽  
Balu D. Dherange ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Biological Investigation ◽  
Design Synthesis

scholarly journals Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4107
Author(s):  
Lanchang Gao ◽  
Zhengge Yang ◽  
Jiaying Xiong ◽  
Chao Hao ◽  
Ru Ma ◽  
...  
Keyword(s):  
Serotonin Receptors ◽  
Atypical Antipsychotics ◽  
Qt Prolongation ◽  
Biological Investigation ◽  
Design Synthesis ◽  
Receptor Affinity ◽  
High Affinity ◽  
Behavioral Studies ◽  
Flavone Derivatives

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

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