Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

Abstract

The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, , inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. also inhibited the growth of NCI-H1975 lung cancer cells at IC = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with . By measuring the conjugate addition product formed by and GSH, we obtained a reaction rate constant of 302.5 × 10 min, which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.

Recent advances in the development of covalent inhibitors

“…5c). 28 In addition, they obtained a reaction rate constant of 302.5 × 10 −3 min −1 by measuring the conjugated adduct formed by the allenamide functional group and GSH. The formation of the conjugated adduct between the allenamide functional group and GSH was about 7- to 28-fold higher than that of the marketed acrylamide-containing covalent drugs.…”

On‐Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool

“…Initially we sought to prepare the modified 2,3‐diaminopropionic acid (Dap) residue 1 (Scheme a) as an allenamide containing building block and investigate methodology for its incorporation during Fmoc solid‐phase peptide synthesis (Fmoc‐SPPS). In recent literature, preparation of terminal allenamides by coupling of 3‐butynoic acid has generally been effected with 2‐chloro‐1‐methylpyridinium iodide (Mukaiyama reagent) . Couplings in SPPS are instead typically performed with uronium reagents derived from hydroxybenzotriazoles such as 1‐hydroxy‐7‐azabenzotriazole (HOAt).…”

“…Using an allenamide handle, Derda and co‐workers were able to prepare a photosensitive peptide macrocyclisation linker by employing a bis‐allenamide functionality . An allenamide has also been utilised as an electrophilic warhead in the design of small molecule irreversible kinase inhibitors and allenamides were found to react with thiols 7‐ to 28‐fold faster than equivalent acrylamides . The thiol–allenamide reaction kinetics are also greater than those of chloro‐ or iodoacetamides …”

Efficient Consecutive Synthesis of Ethyl-2-(4-Aminophenoxy) Acetate, a Precursor for Dual GK and PPARγ Activators, X-ray Structure, Hirshfeld Analysis, and DFT Studies

“…It crystallized in the triclinic crystal system and the P-1 space group with Z=2 and two molecular units as asymmetric formula. The unit cell parameters are a = 8.2104(6)Å, b = 10.3625(9)Å, c = 11.9562(9) Å, α = 101.787 (7), β = 91.849 (6), γ = 102.755(7)°, and V = 968.02(14)Å 3 . Some selected geometric parameters are listed in Table 1.…”

“…Interestingly, compounds III-V showed high capacity to activate both GK and PPARγ concurrently [6]. Over the past decade, the usage of active pharmaceutical ingredients (APIs) has acquired built-up interest thanks to their extensive practice in medicinal chemistry and drug discovery [7][8][9]. Based on previous findings, it was of interest to prepare ethyl 2-(4-aminophenoxy) acetate, a building synthon for multiple-target hypoglycemic action (c.f.…”