Total Synthesis of Desmethyl Jahanyne and Its Lipo-Tetrapeptide Conjugates Derived from Parent Skeleton as BCL-2-Mediated Apoptosis-Inducing Agents

Kallepu, Shivakrishna; Kavitha, Mitta; Yeeravalli, Ragini; Marumudi, Kanakaraju; Jadav, Surender Singh; Das, Amitava; Mainkar, Prathama S.; Chandrasekhar, Srivari

doi:10.1021/acsomega.7b01634

Cited by 16 publications

(15 citation statements)

References 37 publications

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“…Cells were trypsinized and harvested in the presence of protease inhibitor. Samples were subjected to heat at incremental temperatures of 42, 46, 50, 54, 58 and 62 °C for 3 min followed by immediate freeze/thaw in liquid nitrogen and at 25 °C as described previously .…”

Section: Methodsmentioning

confidence: 99%

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

et al. 2019

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Glutathione S‐transferase omega 1 (GSTO1) contributes to the inactivation of a wide range of drug compounds via conjugation to glutathione during phase reactions. Chemotherapy‐induced GSTO1 expression in breast cancer cells leads to chemoresistance and promotes metastasis. In search of novel GSTO1 inhibitors, we identified S2E, a thia‐Michael adduct of sulfonamide chalcone with low LC50 (3.75 ± 0.73 μm) that binds to the active site of GSTO1, as revealed by molecular docking (glide score: −8.1), cellular thermal shift assay and fluorescence quenching assay (Kb ≈ 10 × 105 mol·L−1). Docking studies confirmed molecular interactions between GSTO1 and S2E, and identified the hydrogen bond donor Val‐72 (2.14 Å) and hydrogen bond acceptor Ser‐86 (2.77 Å). Best pharmacophore hypotheses could effectively map S2E and identified the 4‐methyl group of the benzene sulfonamide ring as crucial to its anti‐cancer activity. Lack of a thiophenyl group in another analog, 2e, reduced its efficacy as observed by cytotoxicity and pharmacophore matching. Furthermore, GSTO1 inhibition by S2E, along with tamoxifen, led to a significant increase in apoptosis and decreased migration of aggressive MDA‐MB‐231 cells, as well as significantly decreased migration, invasion and mammosphere formation in sorted breast cancer stem cells (CSCs, CD24−/CD44+). GSTO1 silencing in breast CSCs also significantly increased apoptosis and decreased migration. Mechanistically, GSTO1 inhibition activated the c‐Jun N‐terminal kinase stress kinase, inducing a mitochondrial apoptosis signaling pathway in breast CSCs via the pro‐apoptotic proteins BAX, cytochrome c and cleaved caspase 3. Our study elucidated the role of the GSTO1 inhibitor S2E as a potential therapeutic strategy for preventing chemotherapy‐induced breast CSC‐mediated cancer metastasis and recurrence.

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Section: Methodsmentioning

confidence: 99%

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

et al. 2019

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“…Marinopyrrole A (Maritoclax) is a natural product derived from marine streptomycetes that appears to specifically bind Mcl-1 and target it for proteosomal degradation [ 47 ]. Some synthetic analogues of the marine natural compound jahanyne, isolated from Lyngbya sp., were shown to induce apoptosis in cancer cells by binding Bcl-2 [ 48 ]. The marine natural compound renieramycin M has been shown to downregulate Mcl-1 and Bcl-2 expression in a p53 dependent manner in cancer cells and sensitize them to undergo anoikis [ 49 ].…”

Section: Caspase Dependent Apoptosismentioning

confidence: 99%

Regulated Cell Death Signaling Pathways and Marine Natural Products That Target Them

Guzmán

2019

Marine Drugs

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Our understanding of cell death used to consist in necrosis, an unregulated form, and apoptosis, regulated cell death. That understanding expanded to acknowledge that apoptosis happens through the intrinsic or extrinsic pathways. Actually, many other regulated cell death processes exist, including necroptosis, a regulated form of necrosis, and autophagy-dependent cell death. We also understand that apoptosis occurs beyond the intrinsic and extrinsic pathways with caspase independent forms of apoptosis existing. Our knowledge of the signaling continues to grow, and with that, so does our ability to target different parts of the pathways with small molecules. Marine natural products co-evolve with their targets, and these unique molecules have complex structures with exquisite biological activities and specificities. This article offers a review of our current understanding of the signaling pathways regulating cell death, and highlights marine natural products that can affect these signaling pathways.

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“…The data from the initial MTT assays revealed that jahanyne inhibited the growth of both HL60 cells and HeLa cells with an IC 50 (half-inhibitory concentration) value at the micromolar level and could induce apoptosis in HeLa cells. The bolaamphiphile-mimicking structure of jahanyne and its potent anticancer activity have attracted attention not only from the synthetic community but also from the biological community [19][20][21][22]. Chandrasekhar et al first completed the total synthesis of desmethyl jahanyne [19].…”

Section: Introductionmentioning

confidence: 99%

“…The bolaamphiphile-mimicking structure of jahanyne and its potent anticancer activity have attracted attention not only from the synthetic community but also from the biological community [19][20][21][22]. Chandrasekhar et al first completed the total synthesis of desmethyl jahanyne [19]. Preliminary MTT biological assays of desmethyl jahanyne and synthetic intermediates indicated that the N-methyl group and terminal alkynyl fatty acid motifs were essential for maintaining jahanyne's inhibitory activities against cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Jahanyne Analogs as Cell Cycle Arrest Inducers

Gong²,

Li³

et al. 2020

Marine Drugs

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Jahanyne, a lipopeptide with a unique terminal alkynyl and OEP (2-(1-oxo-ethyl)-pyrrolidine) moiety, exhibits anticancer activity. We synthesized jahanyne and analogs modified at the OEP moiety, employing an α-fluoromethyl ketone (FMK) strategy. Preliminary bioassays indicated that compound 1b (FMK–jahanyne) exhibited decreased activities to varying degrees against most of the cancer cells tested, whereas the introduction of a fluorine atom to the α-position of a hydroxyl group (2b) enhanced activities against all lung cancer cells. Moreover, jahanyne and 2b could induce G0/G1 cell cycle arrest in a concentration-dependent manner.

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Total Synthesis of Desmethyl Jahanyne and Its Lipo-Tetrapeptide Conjugates Derived from Parent Skeleton as BCL-2-Mediated Apoptosis-Inducing Agents

Cited by 16 publications

References 37 publications

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

Regulated Cell Death Signaling Pathways and Marine Natural Products That Target Them

Design, Synthesis and Biological Evaluation of Jahanyne Analogs as Cell Cycle Arrest Inducers

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