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1.
Molecules ; 29(3)2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38338390

ABSTRACT

Diacylhydrazine bridged anthranilic acids with aryl and heteroaryl domains have been synthesized as the open flexible scaffold of arylamide quinazolinones in order to investigate flexibility versus rigidity towards DNA photocleavage and sensitivity. Most of the compounds have been synthesized via the in situ formation of their anthraniloyl chloride and subsequent reaction with the desired hydrazide and were obtained as precipitates, in moderate yields. All compounds showed high UV-A light absorption and are eligible for DNA photocleavage studies under this "harmless" irradiation. Despite their reduced UV-B light absorption, a first screening indicated the necessity of a halogen at the p-position in relation to the amine group and the lack of an electron-withdrawing group on the aryl group. These characteristics, in general, remained under UV-A light, rendering these compounds as a novel class of UV-A-triggered DNA photocleavers. The best photocleaver, the compound 9, was active at concentrations as low as 2 µΜ. The 5-Nitro-anthranilic derivatives were inactive, giving the opposite results to their related rigid quinazolinones. Molecular docking studies with DNA showed possible interaction sites, whereas cytotoxicity experiments indicated the iodo derivative 17 as a potent cytotoxic agent and the compound 9 as a slight phototoxic compound.


Subject(s)
Antineoplastic Agents , Melanoma , Humans , Molecular Docking Simulation , Melanoma/drug therapy , DNA/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Quinazolinones , Structure-Activity Relationship , Molecular Structure , Drug Screening Assays, Antitumor
2.
Molecules ; 29(1)2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38202674

ABSTRACT

Isoxazolidine, isoxazole, and isoquinolinone rings are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, facile and efficient pathways have been developed for the preparation of fused frameworks bearing those heterocycles. The successful approaches for both isoxazolidine/isoquinolinone and isoxazole/isoquinolinone hybrid syntheses relied initially on 1,3-dipolar cycloadditions of nitrones and nitrile oxides to indenone and 2-propargylbenzamide, respectively. The construction of the isoquinolinone lactam system followed by performing a selective Schmidt reaction for isoxazolidine derivatives (two steps overall), whereas the isoxazole lactams were reached via an Ullmann-type cyclisation (three steps overall). Key observations were made regarding the stereo- and regioselectivities of the reactions employed, and small libraries of the targeted hybrids were prepared, demonstrating the general applicability of these strategies.

3.
J Org Chem ; 87(2): 1313-1324, 2022 01 21.
Article in English | MEDLINE | ID: mdl-34936369

ABSTRACT

Chabrolobenzoquinone H (1), a meroditerpene metabolite with cytotoxic activity, is synthesized via a stereoselective Julia-Kocienski olefination between a chiral pool derived aliphatic PT-sulfone and a benzoquinone aldehyde partner. The latter was obtained via consecutive chain extension steps involving a Stille coupling and a stereospecific olefin cross-metathesis reaction followed by malonic ester synthesis and a Krapcho decarboxylation. Furthermore, this total synthesis securely determined the absolute configuration of the targeted natural product.


Subject(s)
Alkenes , Biological Products , Aldehydes , Stereoisomerism , Sulfones
4.
J Org Chem ; 86(15): 10440-10454, 2021 08 06.
Article in English | MEDLINE | ID: mdl-34247481

ABSTRACT

The total synthesis of cytotoxic meroditerpenoid naphthoquinone derivative chabrolonaphthoquinone B (1) in an enantiospecific manner is divulged using a chiral pool approach. The key step of our synthetic route is a modified Julia olefination between a sulfone-bearing aliphatic fragment and a Diels-Alder-derived aromatic aldehyde, leading to the stereoselective construction of the E-trisubstituted double bond.


Subject(s)
Naphthoquinones , Aldehydes , Stereoisomerism , Sulfones
5.
J Org Chem ; 79(14): 6646-54, 2014 Jul 18.
Article in English | MEDLINE | ID: mdl-24967505

ABSTRACT

Potassium aeshynomate (1) is the leaf-opening factor of the nyctinastic plant Aeshynomene indica L. In this article a convenient and efficient strategy for the total synthesis of enantiomerically pure 1 is described, starting from the l-arabinose derived chiron ent-6. The realized synthetic scheme involves a postcoupling oxidation approach and securely determines the absolute configuration of the targeted natural product, which remained unknown until now.


Subject(s)
Azadirachta/chemistry , Butyrates/chemical synthesis , Phenols/chemical synthesis , Butyrates/chemistry , Molecular Conformation , Phenols/chemistry , Plant Leaves/chemistry , Stereoisomerism
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