Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents

A library of structurally related coumarins was generated through synthesis reactions and chemical modification reactions to obtain derivatives with antiproliferative activity both in vivo and in vitro. Out of a total of 35 structurally related coumarin derivatives, seven of them showed inhibitory activity in in vitro tests against Taq DNA polymerase with IC50 values lower than 250 μM. The derivatives 4-(chloromethyl)-5,7-dihydroxy-2H-chromen-2-one (2d) and 4-((acetylthio)methyl)-2-oxo-2H-chromen-7-yl acetate (3c) showed the most promising anti-polymerase activity with IC50 values of 20.7 ± 2.10 and 48.25 ± 1.20 μM, respectively. Assays with tumor cell lines (HEK 293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (2c) was the most promising, with an IC50 value of 8.47 μM and a selectivity index of 1.87. In addition, the derivatives were evaluated against Saccharomyces cerevisiae strains that report about common modes of actions, including DNA damage, that are expected for agents that cause replicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)-2H-chromen-2-one (5b) and 7-(3-(oxiran-2-yl)propoxy)-2H-chromen-2-one (5c) caused DNA damage in S. cerevisiae. The O-alkenylepoxy group stands out as that with the most important functionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the in vitro antiretroviral capacity was tested through RT-PCR assays. Derivative 5c showed inhibitory activity below 150 μM with an IC50 value of 134.22 ± 2.37 μM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.This research was supported by CONICET (PIP 11220200101091CO 2021-2023), PICT 2017-0785 Type D of the National Agency for Scientific and Technological Promotion, UNSL (PROICO 02-2620), and RGLP from AvH Foundation. E.F.B.-H. thanks CONICET for doctoral fellowship and specially to Graphic Designer Bruna-Haupt L. for his help. H.A.G. thanks CONICET for belonging to the CIC. We wish thank to Dr. Di Marco N. I. for the genetic material gently provided. C.R.P. thanks CONICET for belonging to the CIC and Alexander von Humboldt Foundation for the different subsidies. We appreciate language revision by staff from the Instituto de Lenguas, UNSL, and specially Mg. Rezzano S.F.M. thanks to the Spanish Ministry of Science (research grant BFU2017-83954-R), ACIISI (research grant ProID2017010167), and FIISC (research grant PIFIIS19/04). C.G. thanks Ministerio de Ciencia, Innovación y Universidades (MCIU) of Spain-European Regional Development Fund (ERDF) (PGC2018-094503-B-C22). This work is a part of the cotutelled (UNSL-ULL) Ph.D. of E.F.B.-H.Peer reviewe

Lethal and sublethal effects of triterpenes from Junellia aspera (Verbenaceae) on the grain storage insect Tribolium castaneum (Coleoptera: Tenebrionidae) Efectos letales y subletales de triterpenos aislados de Junellia aspera (Verbenaceae) sobre el insecto de granos almacenados Tribolium castaneum (Coleoptera: Tenebrionidae)

Duration of the pupal stage, toxic activity and nutritional indices induced by oleanolic acid (I), maslinic acid (II), and daucosterol (III) isolated from the native plant Junellia aspera and chemical derivatives, were determinated on larvae, and adults of Tribolium castaneum (Herbst). The current study shows that these triterpenes acts as acute toxic compounds when were applied topically and/or incorporated into the food of the red flour beetle. Nevertheless, no activity related with the nutritional status of this insect was produced.Se determinó la duración del estado pupal, actividad tóxica e índices nutricionales sobre larvas y adultos de Tribolium castaneum (Herbst) inducidos por ácido oleanólico (I), ácido maslínico (II) y daucosterol (III) aislados de Junellia aspera y derivados químicos. Se demostró que los triterpenos evaluados actúan como tóxicos agudos cuando se aplican por topicación y/o son incorporados en el alimento. Los compuestos ensayados no presentaron actividad relacionada con el estado nutricional de los insectos

Lethal and sublethal effects of triterpenes from Junellia aspera (Verbenaceae) on the grain storage insect Tribolium castaneum (Coleoptera: Tenebrionidae)

Se determinó la duración del estado pupal, actividad tóxica e índices nutricionales sobre larvas y adultos de Tribolium castaneum (Herbst) inducidos por ácido oleanólico (I), ácido maslínico (II) y daucosterol (III) aislados de Junellia aspera y derivados químicos. Se demostró que los triterpenos evaluados actúan como tóxicos agudos cuando se aplican por topicación y/o son incorporados en el alimento. Los compuestos ensayados no presentaron actividad relacionada con el estado nutricional de los insectos

Enhancement of Antiproliferative Activity by Molecular Simplification of Catalpol

Two iridoid scaffolds were synthesized enantioselectively using as key step an l-proline-catalyzed α-formyl oxidation. The in vitro antiproliferative activities were evaluated against a representative panel of human solid tumor cell lines. Both iridoids induced considerably growth inhibition in the range 0.38–1.86 μM. Cell cycle studies for these compounds showed the induction of cell cycle arrest at the G1 phase. This result was consistent with a decrease in the expression of cyclin D1. Damaged cells underwent apoptosis as indicated by specific Annexin V staining.Peer reviewe

Enhancement of antiproliferative activity by molecular simplification of catalpol

Two iridoid scaffolds were synthesized enantioselectively using as key step an l-proline-catalyzed α-formyl oxidation. The in vitro antiproliferative activities were evaluated against a representative panel of human solid tumor cell lines. Both iridoids induced considerably growth inhibition in the range 0.38-1.86 μM. Cell cycle studies for these compounds showed the induction of cell cycle arrest at the G1 phase. This result was consistent with a decrease in the expression of cyclin D1. Damaged cells underwent apoptosis as indicated by specific Annexin V staining. © 2010 Elsevier Ltd. All rights reserved.This research was supported by the Spanish MEC co-financed by the European Regional Development Fund (CTQ2008-06806-C02-01/BQU), and the Canary Islands ACIISI (PI 2007/021) co-financed by the European FEDER; the Spanish MSC (RTICC RD06/0020/1046 and RD06/0020/0041) and FUNCIS (REDESFAC PI 01/06 and 35/ 06); the Argentinian UNSL (22/Q505), CONICET (PIP 6228) and ANPCyT (PICT-10714, 9759). C.R.P. and C.E.T. belong to CIC-CONICET. L.G.L. thanks the Spanish MSC-FIS for a postdoctoral contract. C.G. and J.M.P. thank the Spanish MEC-FSE for Ramón y Cajal contracts.Peer Reviewe