Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

“…Encouraged by scattered reports on N-acyl-Pictet-Spengler reactions using N-alkoxycarbonyl activation [10,15,[18][19][20][21] (noteworthy, N-Boc is not reliably resistant to the strongly acidic cyclization conditions [22,23]) we further intended to replace the unstable and poorly accessible arylacetaldehyde building blocks [19,22] by more common equivalents, and ended up with ω-methoxystyrenes [18], which have been demonstrated to be advantageous arylacetaldehyde equivalents in strongly acidic, anhydrous media, used for N-acyl-Pictet-Spengler [18] and Povarov [23] reactions before. In order to avoid tedious protective group manipulations in the synthesis of alkaloids bearing free phenolic groups (e.g., with commonly used isopropoxy [19], TIPS or benzyl [24], or benzoyl [25] protection) we investigated the utilization of the ethoxycarbonyl group for phenol protection.…”

“…In continuation of our recent work on the chemistry and pharmacology of benzylisoquinolines and related compounds [6][7][8][9][10][11][12][13][14] we investigated truncated analogues of the bisbenzylisoquino-line alkaloid tetrandrine as blockers of the calcium channel twopore channel 2 (TPC2), and identified 1-benzyl-1,2,3,4-tetrahydroisoquinolines bearing phenoxy and benzyloxy substituents (SG-005, SG-094; for structures of bioactive compounds mentioned in this text, see Figure S1 in Supporting Information File 1) on both aromatic rings as potent blockers with promising antitumor activity [15]. In this work we took advantage of the hitherto less explored N-acyl-Pictet-Spengler reaction and related chemistry based on the seminal work of Speckamp [16], where an N-acyl residue at the arylethylamine building block leads to enhanced cyclization rates due to the acid-mediated formation of highly electrophilic N-acyliminium intermediates [17].…”

“…As a special aspect, we used a carbamate unit (instead of the commonly used carboxamide), ending up with 1-benzyl-1,2,3,4-tetrahydroisoquinolines bearing an N-ethoxycarbonyl residue, which in turn was easily converted directly into an N-methyl group by lithium alanate reduction [18,19]. In a novel total synthesis of the racemic alkaloid N-methylcoclaurine (1) performed in this course we also used the ethoxycarbonyl group successfully for protection of two phenolic groups at two different rings during the N-acyl-Pictet-Spengler reaction [15]. This prompted us to investigate the generality of this approach (dual function of the ethoxycarbonyl residue as activating group for the Pictet-Spengler reaction and as protective group for phenolic groups).…”

Prognostic Value and Immune Infiltration of ARMC10 in Pancreatic Adenocarcinoma Via Integrated Bioinformatics Analyses

“…Several studies have illustrated the role of glutamate receptor in the pathophysiology mechanisms underlying multiple cancers, including breast cancer, glioblastoma, squamous cell lung cancer, prostate cancer, bladder cancer and melanoma [30][31][32][33][34][35]. Besides, researches have demonstrated the critical role of cation channels in the progression of various type of cancer, especially transient receptor potential cation channel subfamily V member 4 (TRPV4) [36-38], transient receptor potential cation channel subfamily M member 7/8 (TRPM7/8) [39][40][41][42] and two-pore channel 2 (TPC2) [43,44]. TPC2 is one of the cation channels located on endolysosomal membranes that could speed up movement between organelles and regulate phagocytosis, autophagy and lysosomal exocytosis [43].…”

“…TPC2 is one of the cation channels located on endolysosomal membranes that could speed up movement between organelles and regulate phagocytosis, autophagy and lysosomal exocytosis [43]. In HCC, TPC2 knockout inhibited cell proliferation and tumor growth through affecting energy metabolism [44]. Another nonselective cation channel TRPM7 involved in Ca 2+ and Mg 2+ homeostasis mainteinance has been found to manage cell differentiation, proliferation and migration.…”