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Dual-acting and Multi-targeting Therapeutic Agents

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 2616

Special Issue Editor


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School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive, NW, Atlanta, GA 30332-0400, USA
Interests: design of targeted epigenetic modifying small molecules; design of tissue selective anti-fibrosis small molecules; design of selective TBK1/IKKe inhibitors; molecular delivery – cell-selective delivery of functional nanoparticles; nucleic acid biochemistry and biophysics – interaction of RNAs with small molecules
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Special Issue Information

Dear Colleagues,

The one-ligand-one-target-one-disease approach is a true and tested drug design principle that has successfully furnished therapeutic agents for several human and veterinary indications. An open secret is that drugs rarely interact with just one target—i.e., they are pleiotropic. Pleiotropy is a two-edged sword as it could be the cause of adverse side effects or vital to the therapeutic effects of the drugs. The recognition of the positive attributes of pleiotropy has given rise to interest in intentionally designed dual- and/or multi-acting drugs (polypharmacological agents). The underpinning objective of research in this field is to identify a new generation of polypharmacological agents that are more efficacious in treating complex diseases such as cancer, metabolic, immunological, and neurological disorders. Major advances have been made in the last decade with the successful introduction of several deliberately designed polypharmacological agents into clinical use. The goal of this Special Issue of Molecules is to provide a medium for researchers to share their new findings on the identification of a new generation of polypharmacological agents, and to appraise the current state of knowledge and the challenges to be addressed in the future.

Prof. Adegboyega K. Oyelere
Guest Editor

Manuscript Submission Information

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Keywords

  • Dual-acting therapeutic agents
  • Multi-targeting therapeutic agents
  • Designed multiple ligands
  • Pleiotropy
  • Complex diseases

Published Papers (1 paper)

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Research

24 pages, 2671 KiB  
Article
Evaluation of Cytotoxicity and α-Glucosidase Inhibitory Activity of Amide and Polyamino-Derivatives of Lupane Triterpenoids
by Oxana B. Kazakova, Gul’nara V. Giniyatullina, Akhat G. Mustafin, Denis A. Babkov, Elena V. Sokolova and Alexander A. Spasov
Molecules 2020, 25(20), 4833; https://doi.org/10.3390/molecules25204833 - 20 Oct 2020
Cited by 26 | Viewed by 2315
Abstract
A series of two new and twenty earlier synthesized branched extra-amino-triterpenoids obtained by the direct coupling of betulinic/betulonic acids with polymethylenpolyamines, or by the cyanoethylation of lupane type alcohols, oximes, amines, and amides with the following reduction were evaluated for cytotoxicity toward the [...] Read more.
A series of two new and twenty earlier synthesized branched extra-amino-triterpenoids obtained by the direct coupling of betulinic/betulonic acids with polymethylenpolyamines, or by the cyanoethylation of lupane type alcohols, oximes, amines, and amides with the following reduction were evaluated for cytotoxicity toward the NCI-60 cancer cell line panel, α-glucosidase inhibitory, and antimicrobial activities. Lupane carboxamides, conjugates with diaminopropane, triethylenetetramine, and branched C3-cyanoethylated polyamine methyl betulonate showed high cytotoxic activity against most of the tested cancer cell lines with GI50 that ranged from 1.09 to 54.40 µM. Betulonic acid C28-conjugate with triethylenetetramine and C3,C28-bis-aminopropoxy-betulin were found to be potent micromolar inhibitors of yeast α-glucosidase and to simultaneously inhibit the endosomal reticulum α-glucosidase, rendering them as potentially capable to suppress tumor invasiveness and neovascularization, in addition to the direct cytotoxicity. Plausible mechanisms of cytotoxic action and underlying disrupted molecular pathways were elucidated with CellMinner pattern analysis and Gene Ontology enrichment analysis, according to which the lead compounds exert multi-target antiproliferative activity associated with oxidative stress induction and chromatin structure alteration. The betulonic acid diethylentriamine conjugate showed partial activity against methicillin-resistant S. aureus and the fungi C. neoformans. These results show that triterpenic polyamines, being analogs of steroidal squalamine and trodusquemine, are important substances for the search of new drugs with anticancer, antidiabetic, and antimicrobial activities. Full article
(This article belongs to the Special Issue Dual-acting and Multi-targeting Therapeutic Agents)
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