A cytotoxic survey on 2‐amino‐1H‐imidazol based synthetic marine sponge alkaloid analogues

Abstract

Here, we describe the synthesis and biologic activity evaluation of 20 novel synthetic marine sponge alkaloid analogues with 2-amino-1H-imidazol (2-AI) core. Cytotoxicity was tested on murine 4T1 breast cancer, A549 human lung cancer, and HL-60 human myeloid leukemia cells by the resazurin assay. A total of 18 of 20 compounds showed cytotoxic effect on the cancer cell lines with different potential. Viability of healthy human fibroblasts and peripheral blood mononuclear cells upon treatment was less hampered compared to cancer cell lines supporting tumor cell specific cytotoxicity of our compounds. The most cytotoxic compounds resulted the following IC 50 values 28: 2.91 µM on HL-60 cells, and 29: 3.1 µM on 4T1 cells. The A549 cells were less sensitive to the treatments with IC 50 15 µM for both 28 and 29. Flow cytometry demonstrated the apoptotic effect of the most active seven compounds inducing phosphatidylserine exposure and sub-G1 fragmentation of nuclear DNA. Cell cycle arrest was also observed. Four compounds caused depolarization of the mitochondrial membrane potential as an early event of apoptosis. Two lead compounds inhibited tumor growth in vivo in the 4T1 triple negative breast cancer and A549 human lung adenocarcinoma xenograft models. Novel marine sponge alkaloid analogues are demonstrated as potential anticancer agents for further development.

Natural Products Derived from Marine Sponges with Antitumor Potential against Lung Cancer: A Systematic Review

“…The mechanism of action was investigated using the myeloid leukemia cell line HL-60, wherein cell cycle arrest, apoptosis, and depolarization of the mitochondrial membrane potential were observed. In an A549 xenograft model, the tested compound demonstrated a notable reduction in tumor growth to 354 ± 15 mm 3 compared to untreated mice with 553 ± 66 mm 3 [ 58 ].…”

“…Furthermore, it should be noted that triterpenoids are one of the most abundant secondary metabolites in marine organisms and have previously been tested with high preclinical efficacy in animal models [ 61 ]. Finally, peloruside A (a polyketide, compound 53 ) and alkaloid derivatives with a 2-amino-1H-imidazole core were tested in xenograft models from the H460 and A549 tumor lines, respectively, showing an ability to inhibit tumor growth without any remarkable systemic toxicity [ 49 , 58 ].…”

“… [ 56 ] Ianthella basta bastadin-6 ( 72 ), bastadin-9 ( 73 ), bastadin-16 ( 74 ), methyl-[2-hydroxyimino-3-(4-hydroxyphenyl)]-propionate ( 75 ), methyl-[2-hydroxyimino-3-(3,5-dibromo-4-hydroxyphenyl)]-propionate ( 76 ), norbromohemibastadin-1 ( 77 ), L-tyrosine-tyramide A ( 78 ), and 5,5′-dibromohemibastadin-1 ( 79 ) Bastadins 72 – 74 : Isolation 4 – 8 : Chemical synthesis A549 (NSCLC) 72 : 3 μM 73 : 7 μM 74 : 8 μM 75 – 78 : >100 μM 79 : 68 μM (72 h) ✗ NR [ 57 ] NR alkaloid analogs with 2-amino-1H-imidazole core Alkaloid Chemical synthesis A549 (NSCLC) 14.15–43.72 μM (72 h) ✓ Inhibition of tumor growth in A549 xenograft models. [ 58 ] * in vivo in lung cancer; not reported, NR; tumor growth inhibition, TGI; non-small-cell lung cancer, NSCLC; non-tumoral, NT; phosphatidylinositol 3-kinase, PI3K; protein kinase B, Akt; serine/threonine-protein kinase mTOR, mTOR; cyclin-dependent kinase inhibitor 1B, p27; poly (ADP-ribose) polymerase, PARP; reactive oxygen species, ROS; microtubule-associated proteins 1A/1B light chain 3B, LC3B; autophagy-related 5, Atg5; tumor protein P53, p53; growth arrest and DNA damage inducible alpha, GADD45α; cyclin-dependent kinase-1, CDC2; cell division cycle 25C, CDC25C; no in vivo evaluation in lung cancer, ✗; in vivo evaluation in lung cancer, ✓; increase, ↑; decrease, ↓. …”

“…Of the 33 articles included in this systematic review, only 5 analyzed the in vivo effects of these compounds in different murine models [ 17 , 29 , 49 , 57 , 58 ]. In fact, approximately 95% of recently developed anticancer drugs ultimately prove unsuccessful in clinical trials despite exhibiting robust anticancer effects in established in vitro preclinical models [ 69 ].…”

Introduction of an Ultraviolet C-Irradiated 4T1 Murine Breast Cancer Whole-Cell Vaccine Model

“…The viability of the UVC-irradiated 4T1 cells was measured using the resazurin assay, as described previously [ 52 , 53 ]. Briefly, the 4T1 cells (8 × 10 3 cells/well) were seeded into 96-well plates (Corning) in RPMI media containing 10% FCS and incubated overnight.…”