Abstract
The sesquiterpene γ-lactone estafiatin 1, the molecule of which has a structure of 3,4α-epoxy-1,5,7α,6β(H)-guai-10(14),11(13)-dien-6,12-olide, is characteristic of plants of the genera Achillea L. and Artemisia L. of the Asteraceae family. This article presents the results of chemical modification for three reaction centers of the estafiatin molecule 1: epoxy cycle, exomethylene group conjugated with γ-lactone carbonyl, and exomethylene group in position C10=C14; and at the same time 33 new derivatives were synthesized, the structures of which were established based on physicochemical constants, spectral data (IR-, PMR-, 13C-NMR), and X-ray diffraction analysis. The stereo- and regiospecificity, as well as the chemoselectivity of the reaction based on estafiatin molecule 1, are discussed. The reactivity of the substrate is significantly influenced by the stereochemistry of its molecule, the nature of the reagent, and the reaction medium. Based on the results of in silico screening, derivatives of estafiatin with high binding energies for both DNA-topoisomerase I and DNA-topoisomerase II were identified. The values of the inhibitory dose of IC50 for estafiatin 1 and its derivatives were determined on cell lines of eight types of tumors. in vivo experiments of the samples made it possible to establish that estafiatin 1 and its derivatives have pronounced antitumor activity against Pliss lymphosarcoma, Walker’s carcinosarcoma, sarcoma 45, sarcoma-180, alveolar liver cancer PC-1, leukemia P-388 and L-1210, and sarcoma-45 resistant to 5-fluorouracil.
Highlights
Guaianolides constitute one of the largest and most widespread groups of natural sesquiterpene γ-lactones of plant origin
According to the literature data [2,4,15], it is into known that a number of chemical can be conditionally divided four groups: transformations were carried out with the estafiatin molecule reactions on the epoxy cycle of estafiatin;1: ozonolysis, catalytic reactionshydrogenation on the trisubstituted double bond; double bond, and hydrogenation, epoxidation,2. selective of the reactions on the exomethylene double the α-methylene-γ-lactone cycle; nucleophilic addition according to the Michael reaction type
One of bond the directions for theC10=C14, epoxy cyclean modification of estafiatin molecule 1 is the on itsofbasis of a derivative with is an the α,β-unsaturated keto group, since such a
Summary
Guaianolides constitute one of the largest and most widespread groups of natural sesquiterpene γ-lactones of plant origin. Most of them have pronounced biological activity [1–3]. Among the most accessible and promising sesquiterpene lactones of the guaiane type, estafiatin 1 has attracted attention (Figure 1) and was first isolated from Artemisia mexicana Willd. Ex Spreng., commonly known in Mexico as “Estafiate”, and its extract as an antihelminthic agent [4]. Estafiatin 1 is a major characteristic terpenoid component of Achillea nobilis L. and Stevia alpina Griseb [5–8]. Achillea nobilis L. is considered renewable plant raw material that has a sustainable operational reserve, which makes it possible to obtain the biologically active sesquiterpene lactone estafiatin on an industrial scale.
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