Littérature scientifique sur le sujet « Dual-warhead »

In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: α-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug-FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead-FGF2 conjugate may overcome the potential acquired resistance of FGFR1-overproducing cancer cells towards single cytotoxic drugs.

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer’s disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10−6 cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.

Linearity, dynamic linearity particularly, is an important parameter in measuring the performance of an accelerometer. The Hopkinson bar has been widely used in calibration of high g accelerometer and other high overloading conditions. Based on one-dimension stress wave theory and superposition theory of elastic waves, designed a Dual Warhead Hopkinson bar to demarcate the dynamic linear parameters of high g micro accelerometer accurately. A finite element model for Hopkinson bar calibration system was created, ANSYS/LS-DYNA was employed to simulate the operation process of Hopkinson bar, and the effects of the projectile's materials, adjustment pads materials and thickness on the acceleration waveform were found.

Gli Antibody-Drug Conjugates (ADC) sono tra i farmaci più promettenti per la terapia mirata antitumorale. Gli ADC sfruttano infatti la capacità degli anticorpi monoclonali di indirizzare il trasporto di molecole citotossiche in modo selettivo al sito del tumore, con un miglioramento dell’efficacia della sicurezza del farmaco citotossico. La porzione linker di collegamento tra l’anticorpo e il farmaco è una componente cruciale di ogni ADC: deve essere stabile in plasma ma instabile all’interno della cellula, permettendo il rilascio del farmaco citotossico solo nell’ambiente citoplasmatico ed evitando un rilascio prematuro nella circolazione sanguigna. In questo progetto di tesi sono stati esplorati numerosi aspetti degli ADC. Abbiamo sviluppato il primo ADC coniugato con un acido idrossamico, l’inibitore dell’enzima istone deacetilasi vorinostat, connesso attraverso un linker degradabile dal metabolismo cellulare. Inoltre, il farmaco è meno potente di quelli solitamente usati negli ADC con una ridotta tossicità sistemica. Per quanto riguarda i “self-immolative spacers”, abbiamo sviluppato un nuovo linker ramificato che permette la possibilità di una sintesi modulare dei vari componenti: tale linker è capace di rilasciare un modello di farmaco citotossico mediante la riduzione di un gruppo disolfuro. Inoltre, sono stati effettuati anche studi verso un approccio convergente alla sintesi dei linker. Oltre al lavoro con i bioconiugati, sono stati sintetizzate alcune impurezze della sintesi industriale dell’agonista dei recettori della melatonina Tasimelteon ed è stata sviluppata una nuova sintesi stereoselettiva dell’agonista dei recettori della sfingosina Ozanimod.
Antibody-Drug Conjugates (ADCs) are emerging as the next generation anticancer therapeutic agents. ADCs take advantage of the specificity of monoclonal antibody to target the delivery of drugs to the tumor site, with an expectation of improving the efficacy and safety of the cytotoxic payload. The linker plays a key role in the development of ADC derivatives and its blood stability as well as its possible degradation into the cell need to be carefully tuned. The synthesis of the linker offers many opportunities for organic chemistry. In this thesis we explored several different aspects of the ADC field. We developed the first ADC charged with a hydroxamic acid payload (the HDAC inhibitor vorinostat), connected through a metabolic sensitive linker. Moreover, the presence of a not highly cytotoxic drug leads to a lower systemic toxicity compared the one generally observed with traditional ADCs. With regard to self-immolative spacers, we designed a novel multifunctional branched linker that offers the opportunity of a modular synthesis of the various ADCs components. This linker is able to release a model of an amine payload from a disulfide trigger moiety. Furthermore, we present also studies towards a convergent approach to the synthesis of the linker. Besides the work on bioconjugates, we report the preparation of several synthetic impurities of the melatonin receptors agonist Tasimelteon and a new protecting group-free stereoselective synthesis of the sphingosine-1-phosphate receptor agonist Ozanimod.