Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold

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

“…This model suggests that the F-ring is probably not essential for Topo-I inhibition. 2,11 A new class of Topo-I inhibitors with the benzo[g] [1]benzopyrano [4,3-b]indol-6(13H)-one scaffold (BBPI) was generated by switching the positions of the pyrrole nitrogen and C-1 of lam-D. The Topo-I inhibitory activities of the selected BBPIs [Nmethyl (41), N-ethyl (42), N-(2-dimethylamino)ethyl (43), and valine ester (44)] derivatives (Fig.…”

“…As a result, there has been a growing interest in this alkaloid family, the bio-origin of which starts with 2-amino-3-(3 ′ ,4 ′ -dihydroxyphenyl)propionic acid, known as DOPA. 2 These DOPA-derived marine pyrrole alkaloids have been extensively studied. 3 Since the discovery of the rst lamellarins A-D in 1985, more than 70 lamellarins and their natural and synthetic analogs have been isolated and described to date.…”

Pyrazole-based lamellarin O analogues: synthesis, biological evaluation and structure–activity relationships

“…5,18 The unbridled key goal is, besides appropriate strategies to synthetically approach these natural compounds, 17,[19][20][21] to create new analogues as innovative drug-like compounds with potent antitumor activities. [22][23][24] Zheng et al reported synthesis and investigation of novel glycosylated lamellarin D compounds wherein glycosyl moieties improve important physicochemical properties of active compounds, especially the solubility in water. 25 Another study revealed A-ring modied lamellarin N analogues as potent noncovalent inhibitors of EGFR T790M/ L858R mutant, which is responsible for non-small cell lung cancer resistance.…”

Toward “E‐Ring‐Free” Lamellarin Analogues: Synthesis and Preliminary Biological Evaluation

“…It was revealed that the presence of hydroxy groups in the structure (especially at C8 and C20 positions), as well as unsaturated D‐ring were beneficial for the cytotoxicity of lamellarins [8b,c] . Subsequently, several studies investigated the importance of the rings in the lamellarin structure [8d–g] . The structural core of hexacyclic lamellarins consists of 1‐arylbenzoindolizine fragment fused with coumarin (Figure 1) and is characterized by the presence of 5 fused rings – A, B, C, D, E. To investigate the effects of the B‐ring on the cytotoxicity of synthetic lamellarins, a small library of lamellarin analogues with an opened lactone B‐ring was tested in human colon (HT‐29), breast (MDA‐MB‐231), and lung (A‐549) cancer cell lines with the exposure time of 72 h [8d] .…”

“…This analogue demonstrated marked cytotoxicity (IC 50 ≈0.113–0.172 μM) in both cell lines, although it was several fold less cytotoxic than camptothecin [8f] . Additionally, a series of F‐ring‐free lamellarin analogues with N‐substituted benzo[ g ][1]benzopyrano[4,3‐ b ]indol‐6(13 H )‐one (BBPI) scaffold was tested against a large panel of cancer cell lines in comparison with irinotecan metabolite SN‐38 and Lamellarin D [8g] . Most of the synthesized compounds demonstrated excellent cytotoxicity in a low nanomolar range, suggesting that F‐ring is not essential [8g] …”