Traceless synthesis of diketopiperazine fused tetrahydro-β-carbolines on soluble polymer support

Abstract

The Pictet-Spengler reaction, using polyethylene glycol immobilized tryptophan ester with a variety of ketones, was achieved by refluxing condition in acidic chloroform. The linear as well as cyclic ketones were employed. All the ketones were reacted within 6-8 h to furnish soluble polymer-supported tetrahydro-β-carboline in good yields. Further expansion at N-terminus of tetrahydro-β-carbolines was achieved through a reaction with chloroacetyl chloride. Finally, the 2,5-diketopiperazine skeleton was constructed over a β-carboline by amination of the resulting N-chloroacetamides and subsequent intramolecular cyclization leading to cleavage of the polymer; constitutes a traceless synthesis of tetracyclic molecular architecture. Significantly, this strategy affords a straightforward and efficient approach for the construction of biological promising molecules with high purity and good yields.

The Pictet-Spengler Reaction Updates Its Habits

“…In the 2011-2015 year range, only two papers concerning an approach in solid phase of the intramolecular P-S reaction appeared [121,122]. In the first one by Chanda et al, polyethylene glycol-immobilized tryptophan ester 102 was combined with a variety of ketones by reflux in acidic chloroform, to give soluble polymer-supported THBCs in good yields [121]. Amination of the N b -chloroacetamide that was obtained by treatment with chloroacetyl chloride, followed by intramolecular cyclization and cleavage of the polymer, finally led to the costruction of a tetracyclic architecture.…”

“…Amination of the N b -chloroacetamide that was obtained by treatment with chloroacetyl chloride, followed by intramolecular cyclization and cleavage of the polymer, finally led to the costruction of a tetracyclic architecture. The reactions and the following synthesis of biologically promising diketopiperazine-fused THBC structures 103 are resumed in Scheme 29 [121]. of natural products and their analogues [113,114].…”

Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

“…Here, we present a comprehensive overview of the recent progress on bio-landscape and structural diversity of compounds containing proline-based DKP motif, which are exploited as privileged peptidomimetic scaffolds for future innovative drug discovery, smart delivery systems, and modern bio-control agents [34][35][36]. We pay special attention to anticancer proline-based DKPs since cancers are main cause of death all over the world, with nearly 10 million deaths in 2020 according to the WHO [37].…”

“…OUCMDZ-1847 [152]. Epicorazine A (112), Epicorazine B (113), Epicorazine C (114), and Exserohilone A (115) were tested for cytotoxic effect against five cancer cell lines: HL-60, HCT-116, A549, K562, and MGC-803 (Table 6, entries [31][32][33][34]. The authors found that Epicorazine A (112) turned out to be the most cytotoxic from the compounds tested with IC 50 values of 0.05 (HL-60), 0.33 (HCT-116), 2.3 (A549), 1.5 (K562), and 2.7 µM (MGC-803) (Table 6, entry 31), and HL-60 cell line was the most susceptible from the lines used in the research.…”

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

“…They have attracted attention in recent years because of their broad biological activities [11–12] and therapeutic applications, ranging from antibiotics [13] to anticancer agents [14]. Moreover, the DKP moiety has been exploited as a peptidomimetic scaffold [15–17]. Structural unification of THBC and DKP pharmacophores has led to new classes of biologically active tetracyclic compounds, both naturally occurring and synthetically made [18].…”