Synthesis and biological activities of chaetocin and its derivatives

2012 ◽  
Vol 84 (6) ◽  
pp. 1369-1378 ◽  
Author(s):  
Mikiko Sodeoka ◽  
Kosuke Dodo ◽  
Yuou Teng ◽  
Katsuya Iuchi ◽  
Yoshitaka Hamashima ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Caspase 3 ◽  
Biological Activities ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Mechanistic Studies ◽  
Anticancer Activities ◽  
Histone Methyltransferases ◽  
Structure Activity ◽  
Apoptosis Inducer

Chaetocin, a natural product isolated from fungi of Chaetomium species, is a member of the epipolythiodiketopiperazines (ETPs), which have various biological activities, including cytostatic and anticancer activities. Recently, the inhibitory activity toward histone methyltransferases (HMTs) was discovered for chaetocin. We previously reported the first total synthesis of chaetocin and various derivatives. During studies on the structure–activity relationship for HMT inhibition, we found that the enantiomer of chaetocin (ent-chaetocin) is a more potent apoptosis inducer than natural chaetocin in human leukemia HL-60 cells. Mechanistic studies showed that ent-chaetocin induces apoptosis through the caspase-8/caspase-3 pathway.

scholarly journals Synthesis of Novel and Potential Antimicrobial, Antioxidant and Anticancer Chalcones and Dihydropyrazoles Bearing Isoxazole Scaffold

Proceedings ◽  
2020 ◽  
Vol 41 (1) ◽  
pp. 16
Author(s):  
Afzal Shaik ◽  
Palleapati Kishor ◽  
Venkata Kancharlapalli
Keyword(s):  
Antioxidant Activities ◽  
Biological Activities ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Antifungal Compound ◽  
Anticancer Activities ◽  
Anticancer Properties ◽  
Structure Activity ◽  
Normal Human Cell ◽  
Normal Human

A series of isoxazole based (E)-1-(isoxazole-5-yl)-3-(substituted phenyl)-prop-2-en-1-ones (chalcones, 3a-3o) and 3-(isoxazol-5-yl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (dihydropyrazoles, 4a-4o) were synthesized, characterized and evaluated for their antimicrobial, antioxidant and anticancer properties. Chalcones exhibited excellent antibacterial and antioxidant activities whereas the dihydropyrazoles shown superior antifungal and anticancer activities. The compound 3l containing 3,4,5-trimethoxy phenyl ring showed the potent antibacterial activity (MIC = 1 µg/mL) as well as the antioxidant activity (IC50 = 5 µg/mL) whereas the dihydropyrazole, 4o (MIC = 0.5 µg/mL) bearing the 2-chloro-3,4-dimethoxyphenyl was the potent antifungal compound identified. The dihydropyrazoles 4n and 4h possessing 2-fluoro-3,4-dimethoxyphenyl and 3,4-dimethoxyphenyl substituents exhibited potent anticancer activity against prostate cancer cell line (DU-145) with MIC 2 and 4 µg/mL respectively. The structure activity relationships had shown that there is a marked influence of both electron withdrawing halogens and electron releasing methoxyl groups on the above biological activities. All the compounds were evaluated for toxicity on normal human cell lines (LO2) and found to be non-toxic. These studies could help to synthesize, explore and identify new isoxazole containing leads for antimicrobial, antioxidant and anticancer properties.

scholarly journals Perkembangan Terapi Kanker Terkait Senyawa Terpineol, P53 dan Caspase 3

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Maya E. W. Moningka
Keyword(s):  
Aspartic Acid ◽  
Cancer Cell ◽  
Anticancer Drug ◽  
Caspase 3 ◽  
Suppressor Gene ◽  
Acid Protease ◽  
Caspase 8 ◽  
Anticancer Activities ◽  
P53 Expression

Abstract: Recent anticancer drug development aims to molecular aspect with more specific target without harming healthy cells. Natural resources have been providing promising new anticancer drugs. Terpineol, an essential oil, is one of the anti-breast cancer candidates. Terpineol can be made from turpentine, which is non-wood product of pine tree latex. Alpha-terpineol isolated from terpineol has an anticancer potency and has been proven to inhibit the growth and induce cancer cell death in vitro by inhibiting NF-κB. P53 is a tumor suppressor gene which triggers apoptosis when irreparable DNA damage occurs. Activity of p53 can be altered and/or inhibited by mutation and inactivation of other oncogenes. The main mechanism underlying apoptosis is caspase (cysteine aspartic acid protease) activity. One of the caspases responsible for apoptosis is caspase 3. This caspase 3 can be activated by either intrinsic (mitochondrial signaling) or extrinsic (death ligand) mechanism; the latter involves caspase 8 and 9. Activated caspase 3 will execute the apoptosis inside the cells. Cytotoxic activity of α-terpineol and its involvement in apoptosis, p53 expression, and caspase 3 activities in cancer cell cultures are still being investigated to determine their anticancer activities and the possibility of anticancer drug development.Keywords: cancer therapy, terpineol, p53, caspase-3 Abstrak: Pengembangan obat antikanker saat ini lebih ditujukan pada aspek molekuler dengan adanya target terapi yang lebih spesifik sehingga lebih aman untuk sel-sel tubuh yang normal. Dewasa ini, eksplorasi terhadap bahan alam untuk kandidat obat antikanker semakin dilirik. Minyak esensial terpineol merupakan salah satu bahan pada komposisi obat antikanker payudara. Terpineol dapat dibuat dari terpentin yang merupakan hasil hutan non kayu dari pohon pinus, dengan cara mengambil getahnya. Dari terpineol diisolasi senyawa α-terpineol yang berpotensi sebagai antikanker serta telah terbukti dapat menghambat pertumbuhan dan menginduksi kematian sel tumor melalui mekanisme yang melibatkan inhibisi aktivitas NFкB. Gen p53 merupakan gen tumor supresor yang memicu terjadinya suatu kematian sel atau apoptosis bila terdapat kerusakan DNA dalam upayanya untuk mengatur proliferasi sel. Selain karena adanya mutasi gen p53, inaktivasi dapat terjadi oleh overekspresi onkogen yang nantinya berikatan dengan p53 dan menghambat kerja gen tersebut. Mekanisme utama yang juga mendasari terjadinya apoptosis ialah aktivitas cysteine aspartic acid protease (caspase). Salah satu caspase yang berperan dalam menginduksi apoptosis ialah caspase 3. Caspase ini dapat diaktifkan melalui mekanisme intrinsik (jalur mitokondrial) maupun ekstrinsik (death ligand), dengan bantuan caspase 8 dan caspase 9. Bila caspase 3 teraktifkan maka sebagai caspase eksekutor, akan melakukan tugasnya untuk mengapoptosis sel. Kajian aktivitas sitotoksik senyawa α-terpineol terhadap suatu cell line, pengaruh senyawa tersebut terhadap proses apoptosis, ekspresi p53, dan aktivitas caspase 3 pada berbagai macam kanker masih terus diteliti dalam perkembangannya sebagai obat anti kanker.Kata kunci: terapi kanker, terpineol, p53, caspase-3

scholarly journals The Synthesis of Aigialomycin D Analogues

2021 ◽  
Author(s):  
◽  
Samuel Z.Y. Ting
Keyword(s):  
Total Synthesis ◽  
Functional Group ◽  
Biological Activities ◽  
Biological Testing ◽  
Hsp90 Inhibition ◽  
Vast Array ◽  
Synthetic Strategy ◽  
Structure Activity ◽  
Expansive Group ◽  
Resorcylic Acid Lactones

<p>Aigialomycin D is a fungal natural product possessing kinase inhibition properties. It is a member of a class of compounds known as the resorcylic acid lactones, a expansive group containing compounds exhibiting a vast array of biological activities. These include kinase and Hsp90 inhibition, highly desirable properties in the drug development field. This research project sought to capitalise on previous work involving the successful total synthesis of aigialomycin D. By developing the synthetic methodology, analogues of aigialomycin D could be prepared for biological testing to obtain valuable structure-activity relationship information. The focus of this thesis involves the successful synthesis of aigialomycin D diastereomer, 5',6'-epi,epi-aigialomycin D and the attempted synthesis of 100-epi-aigialomycin D, via the synthetic strategy developed previously in combination with enantiomeric starting material fragments ... The synthesis of functional group analogues, 6'-oxo-aigialomycin D, 7',8'-cyclopropyl aigialomycin D and 5-chloro-agialomycin D were also attempted via derivatisation of late-stage intermediates in the aigialomycin D synthesis. The thesis herein recounts the successes and failures in the synthesis of various aigialomycin D analogues ...</p>

Berberine Induces Apoptotic Cell Death via Activation of Caspase-3 and -8 in HL-60 Human Leukemia Cells: Nuclear Localization and Structure–Activity Relationships

2017 ◽  
Vol 45 (07) ◽  
pp. 1497-1511 ◽  
Author(s):  
Shinya Okubo ◽  
Takuhiro Uto ◽  
Aya Goto ◽  
Hiroyuki Tanaka ◽  
Tsuyoshi Nishioku ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Antiproliferative Activity ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Leukemia Cells ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Caspase 9

Berberine (BBR), an isoquinoline alkaloid, is a well-known bioactive compound contained in medicinal plants used in traditional and folk medicines. In this study, we investigated the subcellular localization and the apoptotic mechanisms of BBR were elucidated. First, we confirmed the incorporation of BBR into the cell visually. BBR showed antiproliferative activity and promptly localized to the nucleus from 5[Formula: see text]min to 15[Formula: see text]min after BBR treatment in HL-60 human promyelocytic leukemia cells. Next, we examined the antiproliferative activity of BBR (1) and its biosynthetically related compounds (2-7) in HL-60 cells. BBR exerted strongest antiproliferative activity among 1-7 and the results of structures and activity relation suggested that a methylenedioxyl group in ring A, an [Formula: see text]-alkyl group at C-9 position, and the frame of isoquinoline may be necessary for antiproliferative activity. Moreover, BBR showed the most potent antiproliferative activity in HL-60 cells among human cancer and normal cell lines tested. Next, we examined the effect of BBR on molecular events known as apoptosis induction. In HL-60 cells, BBR induced chromatin condensation and DNA fragmentation, and triggered the activation of PARP, caspase-3 and caspase-8 without the activation of caspase-9. BBR-induced DNA fragmentation was abolished by pretreatment with inhibitors against caspase-3 and caspase-8, but not against caspase-9. ERK and p38 were promptly phosphorylated after 15 min of BBR treatment, and this was correlated with time of localization to the nucleus of BBR. These results demonstrated that BBR translocated into nucleus immediately after treatments and induced apoptotic cell death by activation of caspase-3 and caspase-8.

scholarly journals Induction of Apoptotic Cell Death in Human Leukemia U937 Cells by C18 Hydroxy Unsaturated Fatty Acid Isolated from Red Alga Tricleocarpa jejuensis

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 138
Author(s):  
Shijiao Zha ◽  
Mikinori Ueno ◽  
Yan Liang ◽  
Seiji Okada ◽  
Tatsuya Oda ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Dna Fragmentation ◽  
Hydroxy Group ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Red Alga ◽  
Caspase 8 ◽  
Human Leukemia ◽  
U937 Cells ◽  
Cleavage Activity

Our previous studies have found that (±)-(E)-12-hydroxyoctadec-10-enoic acid (HOEA) isolated from the red alga Tricleocarpa jejuensis showed cytotoxic effects on various living organisms including harmful microalgae, Gram-positive bacteria, and mammalian tumor cells. Since natural products with apoptosis-inducing ability can be promising anti-cancer agents, in this study, we investigated the cytotoxic mechanism of HOEA on U937 cells focusing on apoptosis induction. HOEA showed much stronger cytotoxic and cytolytic effects on U937 cells than elaidic acid, which has similar structure but no 12-hydroxy group, suggesting that hydroxy group is important for the cytotoxicity of HOEA. HOEA induced apoptotic nuclear morphological changes, DNA fragmentation, and decrease in mitochondrial membrane potential. Furthermore, time-dependent increase in annexin V+/PI+ cell population in HOEA-treated U937 cells was detected. Among the apoptosis-related reagents, caspase-family inhibitor almost completely inhibited HOEA-induced DNA fragmentation. In the analyses using specific caspase-substrates, extremely high cleavage activity toward caspase-3/7/8 substrate was observed in HOEA-treated U937 cells, and weak activities of caspase-1 and -3 were detected. Analyses using specific caspase inhibitors suggested that caspase-3 and caspase-8 might be predominantly responsible for the cleavage activity. Activation of these caspases were also confirmed by western blotting in which significant levels of cleaved forms of caspase 3, caspase 8, and PARP were detected in HOEA-treated U937 cells. Our results suggest that HOEA is capable of inducing apoptosis in U937 cells in which caspase-3 and caspase-8 might play important roles. Since the cytotoxic effect of HOEA is not strictly specific to tumor cells, development of appropriate drug delivery system for selective tumor targeting is necessary for the clinical applications to reduce the possible side effects.

scholarly journals The Synthesis of Aigialomycin D Analogues

2021 ◽  
Author(s):  
◽  
Samuel Z.Y. Ting
Keyword(s):  
Total Synthesis ◽  
Functional Group ◽  
Biological Activities ◽  
Biological Testing ◽  
Hsp90 Inhibition ◽  
Vast Array ◽  
Synthetic Strategy ◽  
Structure Activity ◽  
Expansive Group ◽  
Resorcylic Acid Lactones

<p>Aigialomycin D is a fungal natural product possessing kinase inhibition properties. It is a member of a class of compounds known as the resorcylic acid lactones, a expansive group containing compounds exhibiting a vast array of biological activities. These include kinase and Hsp90 inhibition, highly desirable properties in the drug development field. This research project sought to capitalise on previous work involving the successful total synthesis of aigialomycin D. By developing the synthetic methodology, analogues of aigialomycin D could be prepared for biological testing to obtain valuable structure-activity relationship information. The focus of this thesis involves the successful synthesis of aigialomycin D diastereomer, 5',6'-epi,epi-aigialomycin D and the attempted synthesis of 100-epi-aigialomycin D, via the synthetic strategy developed previously in combination with enantiomeric starting material fragments ... The synthesis of functional group analogues, 6'-oxo-aigialomycin D, 7',8'-cyclopropyl aigialomycin D and 5-chloro-agialomycin D were also attempted via derivatisation of late-stage intermediates in the aigialomycin D synthesis. The thesis herein recounts the successes and failures in the synthesis of various aigialomycin D analogues ...</p>

scholarly journals 3ʹS,4ʹS-Disenecioylkhellactone from the Roots of Peucedanum Japonicum Induces Apoptosis in HL-60 Cells ​

2020 ◽  
Author(s):  
Kyung-Yun Kang ◽  
Sung-Ju Lee ◽  
Hyun-Ji Kim ◽  
Heonjoong Kang ◽  
Sang-Jip Nam ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Caspase 3 ◽  
Biological Activities ◽  
Leukemia Cell ◽  
Annexin V ◽  
The Philippines ◽  
Cell Counting ◽  
Leukemia Cell Line ◽  
Resonance Spectroscopy ◽  
Human Leukemia

Abstract Background: The root of Peucedanum japonicum is used in traditional medicine in Japan, the Philippines, China, and Korea, and it has been reported to have a variety of biological activities, including anticancer activity. Inducing apoptosis in tumor cells has become a major focus of antitumor drug development; therefore, we studied the apoptotic effects of the MeOH/CH2Cl2 extract of the roots of P. japonicum and its components on HL-60 cells (a human leukemia cell line).Methods: Compounds were purified using solvents with varying polarities followed by column chromatography (reverse phase), and the structures were confirmed using nuclear magnetic resonance spectroscopy. The viabilities of HL-60, A549, and MCF-7 cells were determined using the cell counting kit-8 (CCK-8) assay. Analysis of apoptosis signaling was performed only with HL-60 cells, and cell cycle progression, Annexin V/propidium iodide (PI) staining (analyzed by flow cytometry), the mitochondrial membrane potential (MMP, as analyzed by flow cytometry), and caspase-3, 8, and 9 activity (determined using the caspase-3, -8, and -9 activity kit according to the manufacturer’s protocol) were evaluated.Results: Two coumarin molecules, (-)-isosamidin (1) and 3ʹS,4ʹS disenecioylkhellactone (2), were isolated by bioactivity-guided fractionation. Only compound 2 showed cytotoxicity in HL-60 cells, which occurred due to increases in the sub-G1 population and the initiation of early and late apoptosis as determined by Annexin V/PI staining. In addition, decreases in the MMP were observed in HL-60 cells treated with compound 2. Several apoptotic features were observed, including increased cleavage of caspase-3, -8, and -9. Moreover, treatment with Z-DEVD-FMK (a caspase-3 inhibitor), Z-IETD-FMK (a caspase-8 inhibitor), or Z-LEHD-FMK (a caspase-9 inhibitor) significantly inhibited cell cytotoxicity.Conclusions: We provide evidence that compound 2 induces apoptosis in HL-60 cells.

scholarly journals Synthesis of Flavone Derivatives via N-Amination and Evaluation of Their Anticancer Activities

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2723 ◽  
Author(s):  
Ni Zhang ◽  
Jin Yang ◽  
Ke Li ◽  
Jun Luo ◽  
Su Yang ◽  
...  
Keyword(s):  
Cell Line ◽  
Biological Activities ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Antibacterial Activities ◽  
Anticancer Activities ◽  
Structure Activity ◽  
Ic50 Value ◽  
Erythroleukemia Cell ◽  
Flavone Derivatives

Seventeen new flavone derivatives substituted at the 4′-OH position were designed, synthesized and evaluated for their anticancer and antibacterial activities. Among them, compounds 3, 4, 6f, 6e, 6b, 6c and 6k demonstrated the most potent antiproliferative activities against a human erythroleukemia cell line (HEL) and a prostate cancer cell line (PC3). The results also showed that the IC50 value of compounds 3, 4, 6f, 6e, 6b, 6c and 6k were close to that of the anticancer drug cisplatin (DDP) and lower than that of apigenin. All of the derivatives did not present antibacterial activities. The structure–activity relationships evaluation showed that the configuration of methyl amino acid might affect their biological activities.

scholarly journals Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7

2019 ◽  
Vol 5 (7) ◽  
pp. eaau9433 ◽  
Author(s):  
Scott McComb ◽  
Pik Ki Chan ◽  
Anna Guinot ◽  
Holmfridur Hartmannsdottir ◽  
Silvia Jenni ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Apoptotic Cell ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Double Knockout ◽  
Cytochrome C Release ◽  
Discernible Effect ◽  
Effector Caspase ◽  
Caspase 6 ◽  
Apoptotic Pathways

Apoptosis is a complex multi-step process driven by caspase-dependent proteolytic cleavage cascades. Dysregulation of apoptosis promotes tumorigenesis and limits the efficacy of chemotherapy. To assess the complex interactions among caspases during apoptosis, we disrupted caspase-8, -9, -3, -7, or -6 and combinations thereof, using CRISPR-based genome editing in living human leukemia cells. While loss of apical initiator caspase-8 or -9 partially blocked extrinsic or intrinsic apoptosis, respectively, only combined loss of caspase-3 and -7 fully inhibited both apoptotic pathways, with no discernible effect of caspase-6 deficiency alone or in combination. Caspase-3/7 double knockout cells exhibited almost complete inhibition of caspase-8 or -9 activation. Furthermore, deletion of caspase-3 and -7 decreased mitochondrial depolarization and cytochrome c release upon apoptosis activation. Thus, activation of effector caspase-3 or -7 sets off explosive feedback amplification of upstream apoptotic events, which is a key feature of apoptotic signaling essential for efficient apoptotic cell death.

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