Exploring the RC-106 Chemical Space: Design and Synthesis of Novel (E)-1-(3-Arylbut-2-en-1-yl)-4-(Substituted) Piperazine Derivatives as Potential Anticancer Agents.

Roberta Listro,Michela Cortesi,Mariarosaria Miloso,Marcello Di Giacomo,Guido Cavaletti,Marta Rui,Alessio Malacrida,Giacomo Rossino,Silvia Stotani,Daniela Rossi,Chiara Arienti,Simona Collina,Anna Tesei

doi:10.3389/fchem.2020.00495

Abstract

Despite the fact that significant advances in treatment of common cancers have been achieved over the years, orphan tumors still represent an important unmet medical need. Due to their complex multifactorial origin and limited number of cases, such pathologies often have very limited treatment options and poor prognosis. In the search for new anticancer agents, our group recently identified RC-106, a Sigma receptor modulator endowed with proteasome inhibition activity. This compound showed antiproliferative activity toward different cancer cell lines, among them glioblastoma (GB) and multiple myeloma (MM), two currently unmet medical conditions. In this work, we directed our efforts toward the exploration of chemical space around RC-106 to identify new active compounds potentially useful in cancer treatment. Thanks to a combinatorial approach, we prepared 41 derivatives of the compound and evaluated their cytotoxic potential against MM and GB. Three novel potential anticancer agents have been identified.

Highlights

Cancer represents one of the leading causes of death worldwide (9.6 million deaths in 2018) (“Cancer” n.d.1)
Exploration of chemical space around our previously reported hit RC-106 led us to identify compounds endowed with interesting antitumor properties
Molecules derived from reductive amination and (RA)-106 have different effects on Roswell Park Memorial Institute (RPMI) 8226 and U87-MG cell lines, resulting in RPMI 8226 myeloma cells more sensitive than glioblastoma U87-MG cell line

Summary

Introduction

Cancer represents one of the leading causes of death worldwide (9.6 million deaths in 2018) (“Cancer” n.d.1). Despite the relevant progresses accomplished in the diagnosis and treatment of common cancers, rare tumors are still considered a global issue, in virtue of their negative prognosis (Pillai and Jayasree, 2017). Among the numerous rare cancers listed by the competent organizations, in this work, we focused the attention on glioblastoma (GB) and multiple myeloma (MM), for which effective treatment options are still needed (Shergails et al, 2018; Willenbacher et al, 2018). Signs and symptoms of GB are strictly related to the size and location of the tumor (Esmaeili et al, 2018). Patients in early stages of the pathology have no concerning signs or symptoms, and the diagnosis is confirmed too late (Rajkumar, 2009). Novel target therapies prolonged from 2.5 to over 10 years the life expectancy, nowadays, a concrete cure is still missing (Banaszkiewicz et al, 2019)

Methods

Discussion

Conclusion