Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application

Abstract

During our search for topically-active Caspase-1 inhibitors, we identified a novel class of potent inhibitors based on a 1,3,5-trisubstituted uracil motif equipped with an L-aspartate semi-aldehyde derived warhead. In the literature, the majority of Caspase-1 inhibitors possessing the same warhead have been designed and evaluated for oral administration as the ethyl acetal pro-drug form. For our topical program, the pro-drug acetal form was not fully hydrolysed in the skin and was unstable in many of our standard topical excipients, therefore, we were obliged to focus on the actual hemiacetal drug form of the molecule during our drug discovery program. Our work focuses on both the synthesis and achiral and chiral stability of the final drug molecules in topical excipients.

Nitidumpeptins A and B, Cyclohexapeptides Isolated from Zanthoxylum nitidum var. tomentosum: Structural Elucidation, Total Synthesis, and Antiproliferative Activity in Cancer Cells

“…Nitidumpeptin A (1), a white amorphous powder, gave a molecular formula of C 26 H 34 N 6 O 7 based on HR-ESI-MS data (m/z 543.2550 [M + H] + ) and 13 C NMR data, indicating 13 indices of hydrogen deficiency. In the infrared spectrum of 1, absorption bands at 1716, 1668, and 1646 cm −1 indicated the presence of amide groups.…”

“…The molecular formula of Nitidumpeptin B (2) was established as C 27 H 38 N 6 O 8 by HR-ESI-MS data (m/z 575.2827 [M + H] + ) and 13 C NMR, suggesting 12 indices of hydrogen deficiency. The IR spectrum of 2 displayed strong absorption bands at 1717 and 1645 cm −1 , indicating ester and amide groups in this structure.…”

“…Optical rotation = [α] 20 D -71.4 (c = 0.028; MeOH); IR(KBr) ν max 3465, 3268, 3092, 2952, 2857, 2126, 1563, 1203 cm −1 ; 1 H NMR (400 MHz, DMSO) δ H 12.47 (s, 1H), 8.33 (dt, J = 8.1, 5.8 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.41 (td, J = 7.4, 3.0 Hz, 1H), 7.35−7.16 (m, 2H), 4.32−4.22 (m, 1H), 4.15 (tt, J = 7.6, 3.9 Hz, 1H), 3.80 (dt, J = 11.9, 5.8 Hz, 1H), 3.71 (dd, J = 17.4, 5.8 Hz, 1H), 3.05 (dd, J = 13.7, 3.7 Hz, 1H), 2.80 (dd, J = 13.6, 10.9 Hz, 1H), 1.81−1.67 (m, 1H), 1.48−1.41 (m, 1H), 1.14−1.03 (m, 1H), 0.86 (d, J = 6.8 Hz, 1H), 0.80 (t, J = 7.4 Hz, 1H); 13 Synthesis of Peptidyl Resin 8. 2-CTC resin (1 g, 1.0 mmol/g) was preswollen for 30 min in DCM in a manual SPPS vessel (10 mL).…”

“…1 H NMR (500 MHz, DMSO) δ H 9.04 (d, J = 6.7 Hz, 1H), 8.26 (t, J = 5.1 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 4.8 Hz, 1H), 7.25 (t, J = 7.2 Hz, 2H), 7.18 (td, J = 7.7, 4.0 Hz, 3H), 4.54 (dq, J = 10.6, 7.4 Hz, 2H), 4.39− 4.33 (m, 1H), 3.98−3.89 (m, 4H), 3.29 (dd, J = 14.9, 5.3 Hz, 1H), 3.05 (dd, J = 18.1, 9.5 Hz, 1H), 2.96 (dd, J = 13.3, 7.6 Hz, 1H), 2.91− 2.83 (m, 1H), 2.46 (dd, J = 18.1, 3.9 Hz, 1H), 1.94−1.83 (m, 1H), 1.41 (d, J = 7.3 Hz, 3H), 1.39−1.34 (m, 1H), 1.26−1.16 (m, 1H), 0.84 (d, J = 6.9 Hz, 6H). 13 Total Synthesis of Nitidumpeptin B (2). Synthesis of Cyclic Peptide 10.…”

Trisubstituted push-pull nitro alkenes

“…The first group contains mostly pyrimidine or pyrimidone derivatives (Scheme 9) that are formed by reactions with ureas and amidines. [13][14][15]18,31,34,59,60 There are also examples of other six-membered heterocycles (pyridine 35 and thiadiazine 61 ) prepared in a similar manner. The second group contains structurally more different products (Scheme 10) that are formed by reaction with usually amino heterocycles as 1,3-binucleophiles.…”