Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer’s Disease Potential

Abstract

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer’s disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with Ki in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC50) = 12 μM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced β-amyloid (Aβ)1–40 aggregation (IC50 = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.

Synthesis of Novel Benzo[b][1,6]naphthyridine Derivatives and Investigation of Their Potential as Scaffolds of MAO Inhibitors

“…Compounds 5c – h were then tested on human (h) recombinant MAO A and B using previously reported assays [ 16 , 17 ]. The MAO-B-selective inhibitor, pargyline, was used as the positive control.…”

“…All reagents were purchased from Sigma Aldrich (Milan, Italy). The fluorometric assay was performed as previously described [ 17 ] using human recombinant enzymes from baculovirus-infected insect cells, following the formation of fluorescing 4-hydroxyquinoline from the MAO substrate, kynuramine. Assays were performed in triplicate in 96-well plates (Greiner Bio-One GmbH, Frickenhausen, Germany) using an Infinite M1000 multiplate reader (Tecan, Cernusco sul Naviglio (MI), Italy).…”

“…The interest in this bioactive azaheterocyclic moiety prompted us to further explore its reactivity by synthesizing new original derivatives that could possibly be targeted to the treatment of neurological disorders such as Parkinson’s (PD) and Alzheimer’s (AD) diseases [ 16 , 17 ]. Herein, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[ b ][1,6]naphthyridines ( 3 ) were prepared and used as starting materials to synthesize novel derivatives, e.g., bearing X-substituted phenylethynyl or indolyl groups at C(1).…”

Pyrrolo[2,1-a]isoquinoline scaffolds for developing anti-cancer agents

“…Moreover, it could be noticed that (i) pyrrolo[2,1- a ]isoquinoline' Schiff bases were mostly less cytotoxic than the parent aldehydes, (ii) the adducts bearing a phenyl ring at C-3 were generally less cytotoxic than the corresponding unsubstituted compounds, and (iii) homobivalent Schiff base derivatives were significantly less cytotoxic than the corresponding mono Schiff bases. 89…”

Nature-Inspired 1-phenylpyrrolo[2,1-A]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance

“…Some of previously synthesized 1-Ph-DHPIQ compounds, especially the hydrophobic aldehyde derivatives, like 4a and 4c (data in Table 1) and related imino adducts, proved to be cytotoxic in the tested tumor cell lines with IC 50 s in the low µM range [5,8]. Their mechanism of action has not yet been experimentally investigated, but in silico molecular docking calculations supported, likely as a part of a possible multitarget activity, the propensity of some suitably substituted 1-Ph-DHPIQ-2-carbaldehydes to bind the DNA-topoisomerase I complex [5], potentially blocking the DNA replication.…”