Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy

Abstract

Myrtenal is a natural monoterpene isolated from essential oils of several plants and their derivates have shown to have several biological properties including cytotoxicity. The cytotoxic activity of these derivates are being investigated for their antitumor effect leading to the development of potential anticancer agents. In this study, novels Myrtenyl grafted pseudo-peptides were designed, synthesized and functionally characterized as possible therapeutic agents for cancer treatment. Thirteen novel Myrtenyl grafted pseudo-peptides were prepared in high atom economy and efficiency by a classic Ugi-4CR and sequential post-modification. Their structures were confirmed by NMR, and ESI-MS, and its cytotoxic activity was evaluated in three cancer cell lines and primary CD4+ T cells at different proliferative cycles. Our results revealed that some of these compounds showed significant cytotoxicity against human gastric, breast and colon adenocarcinoma cells lines, but not against human dermal fibroblast cell line. Moreover, from the thirteen novel myrtenyl synthesized the compound (1R,5S)-N-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-N-[2-(cyclohexylamino)-2–oxoethyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide (3b) proved to be the best candidate in terms of acceptable EC50, and Emax values in cancer cell lines and at inducing cytotoxicity in CD4+ T cells undergoing active proliferation, without affecting non-proliferating T cells. Overall, the synthesis and characterization of our Myrtenyl derivates revealed novel potential anticancer candidates with selective cytotoxic activity.

Multicomponent synthesis and photophysical study of novel α,β-unsaturated carbonyl depsipeptides and peptoids

“…UV (DCM, λ max = 227 nm). The spectroscopic data are in agreement with the published data ( Concepción et al, 2020 ).…”

“…The selected carboxylic acids (R-CO 2 H) were benzoic acid for U1 peptoid, cinnamic acid for U2 , (1 R ,5 S )-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxylic acid for U3 , isoquinoline-1-carboxylic acid for U4 , coumarin-3-carboxylic acid for U5 , quinoline-3-carboxylic acid for U6, and coumarin-3-carboxylic acids for U7 (see Figure 3 ). To carry out the reactions, we utilized protic polar solvents (MeOH), which greatly enhanced the solubility of the reactants ( Concepción et al, 2020 ). Reactions were also carried out at high concentrations (1 mM for components) for 24 h. The yields obtained from pure peptoids using U-4CR were greater than those from P-3CR, with the former achieving yields above 55%.…”

Potential molecular mechanisms of myrtenal against colon cancer: A systematic review

“…[ 133 ] The cytotoxic property of myrtenal has been evaluated with different cancer cell lines and experimental animals. [ 134 ] The results obtained from these studies clearly indicate the antioxidant property of myrtenal by scavenging the free radicals and reducing the inflammatory markers Cox 2 and interleukins. [ 87 ] In addition to that, it was found to seize the cell cycle and G1 face during cancer formation and reduce metastatic infiltration of the cancer cells into the lymphatic system.…”

“…In vitro AGS gastric adenocarcinoma cell line [127] Hepatocellular carcinoma • Modulates the phase I and phase II drug metabolizing enzymes • downregulates TNF-α expression…”

Therapeutic Potential of Myrtenal and Its Derivatives—A Review

“…Concepción et al (2020) described several basic structures of myrtenal conjugates such as compound 5 (Figure 7) with high cytotoxicity against cancer cells with EC 50 in the nanomolar range [144]. These novel myrtenal-conjugated pseudo-peptides have been synthesized and investigated as prospective antitumor agents.…”