sp 3 -Rich Glycyrrhetinic Acid Analogues Using Late-Stage Functionalization as Potential Breast Tumor Regressing Agents.

Autor: Kallepu S; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India., Neeli PK; Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India., Mallappa S; Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India., Nagendla NK; Department of Analytical & Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India., Reddy Mudiam MK; Department of Analytical & Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India., Mainkar PS; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India., Kotamraju S; Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India., Chandrasekhar S; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110020, India.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2020 Oct 05; Vol. 15 (19), pp. 1826-1833. Date of Electronic Publication: 2020 Sep 07.
DOI: 10.1002/cmdc.202000400
Abstrakt: Late-stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C-H bonds on pre-existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A-ring, expanding the A-ring and selectively activating one methyl group of the gem-dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA-MB-231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti-invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA-MB-231 cells.
(© 2020 Wiley-VCH GmbH.)
Databáze: MEDLINE
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