Cancer and aging: a multidisciplinary medicinal chemistry approach on relevant biological targets such as proteasome, sirtuins and interleukin 6


Autoria(s): Parenti, Marco Daniele
Contribuinte(s)

Salvioli, Stefano

Data(s)

11/05/2015

Resumo

It is well known that ageing and cancer have common origins due to internal and environmental stress and share some common hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury. Moreover, ageing is involved in a number of events responsible for carcinogenesis and cancer development at the molecular, cellular, and tissue levels. Ageing could represent a “blockbuster” market because the target patient group includes potentially every person; at the same time, oncology has become the largest therapeutic area in the pharmaceutical industry in terms of the number of projects, clinical trials and research and development (R&D) spending, but cancer remains one of the leading causes of mortality worldwide. The overall aim of the work presented in this thesis was the rational design of new compounds able to modulate activity of relevant targets involved in cancer and aging-related pathologies, namely proteasome and immunoproteasome, sirtuins and interleukin 6. These three targets play different roles in human cells, but the modulation of its activity using small molecules could have beneficial effects on one or more aging-related diseases and cancer. We identified new moderately active and selective non-peptidic compounds able to inhibit the activity of both standard and immunoproteasome, as well as novel and selective scaffolds that would bind and inhibit SIRT6 selectively and can be used to sensitize tumor cells to commonly used anticancer agents such gemcitabine and olaparib. Moreover, our virtual screening approach led us also to the discovery of new putative modulators of SIRT3 with interesting in-vitro and cellular activity. Although the selectivity and potency of the identified chemical scaffolds are susceptible to be further improved, these compounds can be considered as highly promising leads for the development of future therapeutics.

Formato

application/pdf

Identificador

http://amsdottorato.unibo.it/6801/1/parenti_marcodaniele_tesi.pdf

urn:nbn:it:unibo-14291

Parenti, Marco Daniele (2015) Cancer and aging: a multidisciplinary medicinal chemistry approach on relevant biological targets such as proteasome, sirtuins and interleukin 6, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Oncologia e patologia sperimentale <http://amsdottorato.unibo.it/view/dottorati/DOT494/>, 27 Ciclo. DOI 10.6092/unibo/amsdottorato/6801.

Idioma(s)

en

Publicador

Alma Mater Studiorum - Università di Bologna

Relação

http://amsdottorato.unibo.it/6801/

Direitos

info:eu-repo/semantics/openAccess

Palavras-Chave #MED/04 Patologia generale
Tipo

Tesi di dottorato

NonPeerReviewed