Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells

Abstract

Akt is a key regulatory protein of cancer stem cells (CSCs) and is responsible for cancer aggressiveness and metastasis. Targeting Akt is beneficial for the development of cancer drugs. renieramycin T (RT) has been reported to have Mcl-1 targeting activity, and the study of the structure-activity relationships (SARs) demonstrated that cyanide and the benzene ring are essential for its effects. In this study, novel derivatives of the RT right-half analog with cyanide and the modified ring were synthesized to further investigate the SARs for improving the anticancer effects of RT analogs and evaluate CSC-suppressing activity through Akt inhibition. Among the five derivatives, a compound with a substituted thiazole structure (DH_25) exerts the most potent anticancer activity in lung cancer cells. It has the ability to induce apoptosis, which is accompanied by an increase in PARP cleavage, a decrease in Bcl-2, and a diminishment of Mcl-1, suggesting that residual Mcl-1 inhibitory effects exist even after modifying the benzene ring to thiazole. Furthermore, DH_25 is found to induce CSC death, as well as a decrease in CSC marker CD133, CSC transcription factor Nanog, and CSC-related oncoprotein c-Myc. Notably, an upstream member of these proteins, Akt and p-Akt, are also downregulated, indicating that Akt can be a potential target of action. Computational molecular docking showing a high-affinity interaction between DH_25 and an Akt at the allosteric binding site supports that DH_25 can bind and inhibit Akt. This study has revealed a novel SAR and CSC inhibitory effect of DH_25 via Akt inhibition, which may encourage further development of RT compounds for cancer therapy.

Dendritic cell therapy for neurospoagioma: Immunomodulation mediated by tumor vaccine

“…We conducted further exploration into the immune regulation of neurospoagioma through DC gene vaccines. CD133, a cell surface antigen, has been identified on the cancer stem cells of various solid tumors, including neurospoagioma [ 57 , 58 ]. The enrichment of CD133-positive neurospoagioma stem cells has been linked to a highly tumorigenic population [ 59 , 60 ], which shows a negative correlation with patient survival.…”

Light-Mediated Transformation of Renieramycins and Semisynthesis of 4′-Pyridinecarbonyl-Substituted Renieramycin-Type Derivatives as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells

“…According to previous studies investigating the structure-cytotoxicity relationship, which employed both in vitro and in silico approaches, the mechanistic pathways underlying the anti-lung cancer effects of marine alkaloids from the tetrahydroisoquinolinequinone family have been elucidated. Specifically, compounds such as 5-O-(N-Boc-L-alanine)-renieramycin T, a renieramycin-ecteinascidin derivative [20], (1R,4R,5S)-10-(benzyloxy)-9-methoxy-8,11-dimethyl-3-(thiazol-5-ylmethyl)-1,2,3,4,5,6-hexahydro-1,5-epimi-nobenzo [d]azocine-4-carbonitrile (DH_25), a right-half C-E ring analog of renieramycins [30], and 22-O-(4′-pyridinecarbonyl) jorunnamycin A, a 4′-pyridinecarbonyl substituted renieramycin-type derivative [29], have demonstrated efficacy against non-small cell lung cancer (NSCLC) cells through modulation of the protein kinase B (Akt), myeloid cell leukemia-1 (MCL-1), and mitogen-activated protein kinase (MAPK) signaling pathways, leading to the induction of apoptosis. The proteins Akt, MCL-1, and MAPK are interconnected targets of cellular signaling networks involved in the regulation of apoptosis.…”

Renieramycin t derivative dh_22 induces apoptosis in lung cancer cells by downregulation of C-Myc protein

“…However, the observed compound was not interacting with residue Trp80 of Akt1 with - stacking interaction, which is one of the key interactions in the allosteric inhibition of Akt (75) The RT derivative DH_22 (Figure 6) is a novel compound synthesized based on the right-half structure of RT, or RM-based hybrid renieramycin-ecteinascidin derivative (28), which was isolated from the Thai blue sponge Xestopongia sp. We synthesized various derivatives of reniramycin from marine natural products as starting materials (76) and evaluated their biological activities. The results indicated that a compound was effective when aromatic rings (especially pyridine rings) were introduced in place of the angelate in the C-1 substituent of reniramycins (77,78).…”