Bridged Peptide Analogue of RA-VII, an Antitumor Bicyclic Hexapeptide

Abstract

A bridged peptide analogue of RA-VII was designed, in which the α carbons of residues 1 and 4 were linked by a tetramethylene chain to restrict the conformational freedom of the backbone of the 18-membered cyclopeptide. This peptide analogue was synthesized by a ring-closing metathesis reaction of [l-2-allylglycine-1, l-2-allylglycine-4]RA-VII and a subsequent hydrogenation of the resulting olefinic compound. Compared with RA-VII, the analogue showed much weaker cytotoxic activity toward human promyelocytic leukemia HL-60 cells and human colon carcinoma HCT-116 cells, which may be accounted for by the difference in the orientation of the Tyr-6 phenyl ring plane between the analogue and RA-VII.

Key words

RA-VII - bouvardin - analogue - conformation - cytotoxicity - Rubia cordifolia

Publication History

Received: 08 September 2022

Accepted after revision: 13 October 2022

Accepted Manuscript online:
13 October 2022

Article published online:
23 November 2022

• References and Notes

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• 16 In the construction of the 18-membered peptide ring of 1 and its analogues, macrocyclization was generally carried out between residues 1 and 6.^{14a, b, e, h–j} In the synthesis of 3, however, macrocyclization between these residues was unsuccessful. Compound 15 did not give 3 under any macrocyclization conditions (DPPA/Et₃N/DMF, EDC·HCl/HOOBt/DMF, or pentafluorophenyl diphenylphosphinate/DIEA/DMF or CH₂Cl₂), whereas macrocyclization of 16 with DPPA/NaHCO₃/DMF gave a cyclized product in 44% yield, although this product was an epimer of 4 at Tyr-6 (Figure 5).
• 17 ¹H (600 MHz) and ¹³C (150 MHz) NMR data of analogue 3 (Figure 6) in chloroform-d at 300 K is given below. Conformer-IAA-1 (α, δ_H 4.52/δ_C 52.4; β_a, δ_H 1.49/δ_C, 29.7; β_b, δ_H 2.39; γ, δ_H 1.29, 1.01, δ_C 22.1, C=O, δ_C 172.5; NH, δ_H 7.45), Ala-2 (α, δ_H 4.64/δ_C 45.8; β, δ_H 1.36 (3 H)/δ_C 6.1; C=O, δ_C 171.5; NH, δ_H 5.91), Tyr-3 (α, δ_H 3.63/δ_C 69.1; β, δ_H 3.45, 3.39/δ_C 32.5; γ, δ_C 130.9; δ, δ_H 7.05 (2 H)/δ_C 130.3 (2 C); ε, δ_H 6.83 (2 H)/δ_C 113.9 (2 C); ζ, δ_C 158.3; C=O, δ_C 168.3; NMe, δ_H 2.93 (3 H)/δ_C 40.5; OMe, δ_H 3.79 (3 H)/δ_C 55.3), AA-4 (α, δ_H 4.83/δ_C 51.9; β_a, δ_H 1.74/δ_C 27.8; β_b, δ_H 2.34; γ, δ_H 1.17, 1.06, δ_C 21.6, C=O, δ_C 172.4; NH, δ_H 7.29), Tyr-5 (α, δ_H 5.31/δ_C 56.4; β_a, δ_H 3.47/δ_C 35.9; β_b, δ_H 3.30; γ, δ_C 132.4; δ_a, δ_H 7.35/δ_C 132.0; δ_b, δ_H 7.50/δ_C 130.6; ε_a, δ_H 7.22/δ_C 127.9; ε_b, δ_H 7.21/δ_C 124.4; ζ, δ_C 159.1; C=O, δ_C 171.4; NMe, δ_H 3.30 (3 H)/δ_C 32.3), Tyr-6 (α, δ_H 3.28/δ_C 70.9; β_a, δ_H 2.96/δ_C 31.0; β_b, δ_H 3.28; γ, δ_C 132.4; δ_a, δ_H 6.64/δ_C 121.4; δ_b, δ_H 4.07/δ_C 117.9; ε_a, δ_H 6.73/δ_C 111.6; ε_b, δ_C 152.9; ζ, δ_C 146.0; C=O, δ_C 167.6; NMe, δ_H 3.20 (3 H)/δ_C 43.2; OMe, δ_H 3.92 (3 H)/δ_C 56.0).Conformer-IIAA-1 (α, δ_H 4.58/δ_C 53.7; β_a, δ_H 1.52/δ_C 30.8; β_b, δ_H 2.14; γ, δ_H 1.21, 1.02, δ_C 23.1, C=O, δ_C 172.5; NH, δ_H 7.83), Ala-2 (α, δ_H 4.94/δ_C 42.8; β, δ_H 0.74 (3 H)/δ_C 17.1; C=O, δ_C 172.6; NH, δ_H 5.93), Tyr-3 (α, δ_H 4.96/δ_C 62.5; β, δ_H 3.16, 2.84/δ_C 33.7; γ, δ_C 128.7; δ, δ_H 7.06 (2 H)/δ_C 130.1 (2 C); ε, δ_H 6.83 (2 H)/δ_C 114.3 (2 C); ζ, δ_C 158.7; C=O, δ_C 166.5; NMe, δ_H 2.98 (3 H)/δ_C 29.1; OMe, δ_H 3.76 (3 H)/δ_C 55.4), AA-4 (α, δ_H 4.98/δ_C 52.1; β_a, δ_H 1.99/δ_C 28.9; β_b, δ_H 1.77; δ_H 1.17 (2 H), δ_C 21.7, C=O, δ_C 172.4; NH, δ_H 8.27), Tyr-5 (α, δ_H 5.35/δ_C 57.2; β_a, δ_H 3.57/δ_C 35.3; β_b, δ_H 3.26; γ, δ_C 132.3; δ_a, δ_H 7.35/δ_C 131.8; δ_b, δ_H 7.54/δ_C 130.5; ε_a, δ_H 7.22/δ_C 127.9; ε_b, δ_H 7.23/δ_C 124.6; ζ, δ_C 159.2; C=O, δ_C 171.8; NMe, δ_H 3.28 (3 H)/δ_C 32.8), Tyr-6 (α, δ_H 3.29/δ_C 71.3; β_a, δ_H 2.96/δ_C 31.1; β_b, δ_H 3.33; γ, δ_C 132.5; δ_a, δ_H 6.66/δ_C 121.4; δ_b, δ_H 4.03/δ_C 118.1; ε_a, δ_H 6.73/δ_C 111.7; ε_b, δ_C 153.0; ζ, δ_C 146.0; C=O, δ_C 167.9; NMe, δ_H 3.20 (3 H)/δ_C 43.1; OMe, δ_H 3.93 (3 H)/δ_C 56.1)
• 18 Morita H, Kondo K, Hitotsuyanagi Y, Takeya K, Itokawa H, Tomioka N, Itai A, Iitaka Y. Tetrahedron 1991; 47: 2757
• 19 The procedure for the cytotoxicity assay has previously been described, see: Inaba Y, Hasuda T, Hitotsuyanagi Y, Aoyagi Y, Fujikawa N, Onozaki A, Watanabe A, Kinoshita T, Takeya K. J. Nat. Prod. 2013; 76: 1085
• 20 Hitotsuyanagi Y, Sasaki S.-i, Matsumoto Y, Yamaguchi K, Itokawa H, Takeya K. J. Am. Chem. Soc. 2003; 125: 7284
• 21 The software used for this calculation was MacroModel ver. 7.0 (Schrödinger Inc.). The Monte Carlo (MC) search was configured using the ‘automatic setup’ routine in MacroModel with all amide configuration in the macrocycle fixed as trans. The calculation consisted of 20,000 MC steps with 1000 iterations per step using the MMFFs force field and the PR conjugate gradient with no solvation.