Design, synthesis and evaluation of antitumor acylated monoaminopyrroloquinazolines

Abstract

Pyrroloquinazoline is a privileged chemical scaffold with diverse biological activities. We recently described a series of N-3 acylated 1,3-diaminopyrroloquinazolines with potent anticancer activities. The N-1 primary amino group in 1,3-diaminopyrroloquinazoline is critical for its inhibitory activity against dihydrofolate reductase (DHFR). In order to design out this unnecessary DHFR inhibition activity and further expand the chemical space associated with pyrroloquinazoline, we removed this N-1 primary amino group. In this report, we describe our design and synthesis of a series of N-3 acylated monoaminopyrroloquinazolines. Biological evaluation of these compounds identified a naphthamide 4a as a potent anticancer agent (GI50 = 88-200 nM), suggesting that removing the N-1 primary amino group in 1,3-diaminopyrroloquinazoline is a useful chemical modification that can be introduced to improve the anticancer activity.

Phosphorylation of Lamin A/C at serine 22 modulates Na v 1.5 function

“…LBL1, which binds Lamin A/C in the N‐terminal region encompassing Ser 22, was identified based on its ability to inhibit the growth of cancer cells (Chao et al, 2017 ; Li et al, 2018 ). LBL1 inhibits the proliferation of cancer cells at micromolar concentrations, so we treated LMNA ‐transfected HEK‐293 cells with 5 and 10 µM LBL1 to determine if that was sufficient to prevent the phosphorylation of Ser 22.…”

“…The A287Lfs frame shift mutation alters the sequence from A287 in the rod domain to the premature stop codon in the Ig‐fold. In contrast, LBI1 binds Lamin A/C in the N‐terminal region encompassing Ser 22 (Chao et al, 2017 ; Li et al, 2018 ).…”

“…Thus, we sought to determine if Ser 22 is involved in the mechanism by which the p.R545H variant affects Na v 1.5 function, with the aim of identifying a potential therapeutic target for CCD patients with similar LMNA mutations. We used a novel small molecule (lamin‐binding ligand, LBL1) that binds Lamin A/C in the N‐terminal region encompassing Ser 22 (Chao et al, 2017 ; Li et al, 2018 ), as well as genetic (Ser 22 modification) approaches to modulate Ser 22 phosphorylation and determine its role in Na v 1.5 function.…”