An Expeditious Modular Hybrid Strategy for the Diversity-Oriented Synthesis of Lamellarins/Azalamellarins with Anticancer Cytotoxicity

Abstract

A modular hybrid strategy has been developed for the diversity-oriented synthesis of lamellarins/azalamellarins. The common pentacyclic pyrrolodihydroisoquinoline lactone/lactam core was formed via the Michael addition/ring closure (Mi-RC) and the copper­(I) thiophene-2-carboxylate (CuTC)-catalyzed C–O/C–N Ullmann coupling. Subsequent direct functionalization at C1, DDQ-mediated C5C6 oxidation, and global deprotection of all benzyl-type O- and N-protecting groups furnished the desired lamellarins/azalamellarins. The late-stage functionalization at C1 provided a handle to accommodate a wider scope of functional groups as they need to tolerate only the DDQ oxidation and global deprotection. Moreover, with the C1-H pyrrole as the late-stage common intermediate, it was also possible to divergently exploit not only its nucleophilic nature to react with some electrophilic species but also some transition-metal-catalyzed cross-coupling reactions (via the intermediacy of the C1-iodopyrrole) to incorporate diversity at this position. Overall, this strategy simplifies the preparation of lamellarins/azalamellarins; including the Mi-RC, these C1-structurally diverse analogues could be prepared efficiently in 6–7 steps from the easily accessed 1-acetoxymethyldihydroisoquinoline and β-nitrocinnamate. Some selected azalamellarins were evaluated for their inhibitory effect against HeLa cervical cancer cells. An acute induction of intrinsic apoptosis was detected and may lead to growth suppression of or cytotoxicity against cancer cells.

Synthesis of Naphthoquinone‐ and Pyrrolo[2,1‐a]isoquinoline‐Fused Heterocycles and Tridemethoxy Lamellarin D

“…The NaHCO 3 ‐mediated Grob coupling of 1‐methylisoquinoline 11 and 3‐nitrocoumarin 17 (prepared from condensation of 2‐hydroxy‐4‐methoxybenzaldehyde with ethyl nitroacetate) [17] in a sealed tube gave the lamellarin pentacyclic core 18 in 30% yield [5c] . Bromination of 18 by NBS in THF at room temperature for 1 h furnished the brominated pentacycle 19 in 85% yield [18] . The Suzuki coupling [19] of 19 with (4‐methoxyphenyl)boronic acid in DME yielded the protected lamellarin 20 in 83% yield.…”

“…[5c] Bromination of 18 by NBS in THF at room temperature for 1 h furnished the brominated pentacycle 19 in 85% yield. [18] The Suzuki coupling [19] of 19 with (4methoxyphenyl)boronic acid in DME yielded the protected lamellarin 20 in 83% yield. Final exhaustive demethylation of 20 with excess of BBr 3 afforded the tridemethoxy lamellarin D ( 16) in 81% yield.…”

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.…”

Titanium-Mediated aza-Nazarov Annulation for the Synthesis of N-Fused Tricycles: A General Method to Access Lamellarin Analogues

“… Of note, after Lamellarin was initially isolated from marine prosobranch mollusk, more than 70 examples of such skeletons have been found up to date, and scientists worldwide have been devoted to investigating their synthetic methodologies and drug properties . In general, there were two common strategies to synthesize such fused [6/6/5] heterocycles: (a) the formation of N-alkylation ylides of isoquinoline and reaction with various inter- or intramolecular unsaturated π-bonds and (b) pyrrole functional group stitching to synthesize Lamellarin scaffolds . Although straightforward and meaningful, both methods suffer from the preinstallation of multifunctional groups, low efficiency of long-step transformation, and harsh conditions often needed.…”