Synthesis and Biological Evaluation of Phaeosphaeride A Derivatives as Antitumor Agents

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell line (IC50 = 1.35 ± 0.69 μM), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 μM, 1.80 μM and 2.00 μM, respectively.

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Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

Medicinal Chemistry ◽

10.2174/1573406416666200420081540 ◽

2020 ◽

Vol 16 ◽

Author(s):

Tran Khac Vu ◽

Nguyen Thi Thanh ◽

Nguyen Van Minh ◽

Nguyen Huong Linh ◽

Nguyen Thi Phương Thao ◽

...

Keyword(s):

Drug Discovery ◽

Cell Lines ◽

Cancer Cell ◽

Hdac Inhibitors ◽

Cancer Cell Lines ◽

Hydroxamic Acids ◽

Biological Evaluation ◽

Hdac Inhibition ◽

Ic50 Value ◽

Mcf 7

Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Method: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)- ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structure-activity. relationships. Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

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Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

Molecules ◽

10.3390/molecules26133923 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3923

Author(s):

Adel A.-H. Abdel-Rahman ◽

Amira K. F. Shaban ◽

Ibrahim F. Nassar ◽

Dina S. EL-Kady ◽

Nasser S. M. Ismail ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Molecular Docking Study ◽

Human Cancer Cell Lines ◽

Hct 116 ◽

Mcf 7

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-−C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.

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Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines

Clinical Epigenetics ◽

10.1186/s13148-021-01026-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Suleyman Vural ◽

Alida Palmisano ◽

William C. Reinhold ◽

Yves Pommier ◽

Beverly A. Teicher ◽

...

Keyword(s):

Dna Methylation ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Chemotherapeutic Agents ◽

Epigenetic Factors ◽

Expression Of Genes ◽

Genes Encoding

Abstract Background Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents. Results We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation. Conclusions Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.

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Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines

Biomedicines ◽

10.3390/biomedicines9010092 ◽

2021 ◽

Vol 9 (1) ◽

pp. 92

Author(s):

Bashir Lawal ◽

Yen-Lin Liu ◽

Ntlotlang Mokgautsi ◽

Harshita Khedkar ◽

Maryam Rachmawati Sumitra ◽

...

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Cancer Cell ◽

Human Tumor ◽

Cancer Cell Lines ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines ◽

Anti Cancer

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein–ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy.

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Design, Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety

Molecules ◽

10.3390/molecules26103041 ◽

2021 ◽

Vol 26 (10) ◽

pp. 3041

Author(s):

Xiaohan Hu ◽

Sheng Tang ◽

Feiyi Yang ◽

Pengwu Zheng ◽

Shan Xu ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Lines ◽

Cancer Cell ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Design Synthesis ◽

Structure Activity ◽

Excellent Activity ◽

Ic50 Values ◽

Mcf 7

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.

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Synthesis, Anticancer Activity, and Molecular Modeling of New Halogenated Spiro[pyrrolidine-thiazolo-oxindoles] Derivatives

Applied Sciences ◽

10.3390/app10062170 ◽

2020 ◽

Vol 10 (6) ◽

pp. 2170 ◽

Cited By ~ 3

Author(s):

Mohammad Shahidul Islam ◽

Abdullah Mohammed Al-Majid ◽

Fardous F. El-Senduny ◽

Farid A. Badria ◽

A. F. M. Motiur Rahman ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Single Step ◽

One Pot ◽

Antiproliferative Effects ◽

Physiochemical Parameters ◽

Hct 116 ◽

Mcf 7

A one-pot, single-step, and an atom-economical process towards the synthesis of highly functionalized spirooxindoles analogues was efficiently conducted to produce a satisfactory chemical yields (70–93%) with excellent relative diastereo-, and regio-selectivity. An in vitro antiproliferative assay was carried out on different cancer cell lines to evaluate the biological activity of the synthesized tetrahydro-1’H-spiro[indoline-3,5’-pyrrolo[1,2-c]thiazol]-2-one 5a–n. The prepared hybrids were then tested in vitro for their antiproliferative effects against three cancer cell lines, namely, HepG2 (liver cancer), MCF-7 (breast cancer), and HCT-116 (colon cancer). The spirooxindole analogue 5g exhibited a broad activity against HepG2, MCF-7, and HCT-116 cell lines of liver, breast, and colorectal cancers when compared to cisplatin. Modeling studies including shape similarity, lipophilicity scores, and physicochemical parameters were calculated. The results of this study indicated that spirooxindole analogue 5g retained a good physiochemical parameters with acceptable lipophilicity scores.

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Cytotoxic Constituents of Pachyrhizus Tuberosus from Peruvian Amazon

Natural Product Communications ◽

10.1177/1934578x1300801022 ◽

2013 ◽

Vol 8 (10) ◽

pp. 1934578X1300801 ◽

Cited By ~ 1

Author(s):

Olga Leuner ◽

Jaroslav Havlik ◽

Milos Budesinsky ◽

Vladimir Vrkoslav ◽

Jessica Chu ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Mtt Assay ◽

Human Cancer ◽

Chemical Constituents ◽

Human Fibroblasts ◽

Cancer Cell Lines ◽

Cytotoxic Effects ◽

Hct 116 ◽

Mcf 7

Investigations into the chemical constituents of the seeds of the neglected tuber crop Pachyrhizus tuberosus (Leguminosae) resulted in the isolation of seven components: five rotenoids [12a-hydroxyerosone (1), 12a-hydroxydolineone (2), erosone (3), 12a-hydroxyrotenone (4) and rotenone (6)], a phenylfuranocoumarin [pachyrrhizine (5)] and an isoflavanone [neotenone (7)]. The compounds were isolated using several chromatography techniques and characterized and verified by NMR and HPLC/MS. The MTT assay was used to examine the selective cytotoxic effects of the methanolic P. tuberosus extract and isolated compounds in two human cancer cell lines [breast (MCF-7) and colorectal (HCT-116)] and in non-transformed human fibroblasts (MRC-5); IC50 values were calculated. The methanolic P. tuberosus extract displayed respectable cytotoxic effects against HCT-116 and MCF-7 cells with IC50 values of 7.3 and 6.3 μg/mL, respectively. Of the compounds, 6 exacted greatest cytotoxicity and selectivity towards the cancer cell lines tested, yielding IC50 values of 0.3 μg/mL against both MCF-7 and HCT-116 cells, and a 6-fold reduced activity against MRC-5 fibroblasts. Compound 4 also demonstrated cytotoxicity against MCF-7 and HCT-116 (1.1 and 1.8 μg/mL, respectively), and reduced cytotoxicity towards MRC-5 cells (7.5 μg/mL). The results revealed from the in vitro cytotoxic MTT assay are worthy of further antitumor investigation.

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Evaluating the Anticancer Potentials of Methanol Extracted Annona muricata Fruit Pulp and Seed(s) Phytochemicals

Clinical Oncology and Research ◽

10.31487/j.cor.2020.08.04 ◽

2020 ◽

pp. 1-8

Author(s):

D. Devananda ◽

Shashanka K Prasad ◽

D. Devananda

Keyword(s):

Traditional Medicine ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Antioxidant Activities ◽

Annona Muricata ◽

Fruit Pulp ◽

Hct 116 ◽

Mcf 7

Annona muricata L. has been widely used in traditional medicine for the treatment of various diseases ranging from fever to cancer. In this study, we evaluate the in vitro anticancer potential of methanol extracted A. muricata fruit pulp (AMPM) and seeds (AMSM) phytochemicals against breast (MCF-7), cervical (HeLa), prostate (PC-3) and colorectal (HCT-116) cancer cell lines. Additionally, the in vitro antiinflammatory and antioxidant activities of the extracts have been carried. The findings suggest that the AMSM is the most potent among the either extracts. Notwithstanding, both AMPM and AMSM showed significant dose and cell line-dependent anticancer potential(s).

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The Effect of Okra (Abelmoschus esculentus (L.) Moench) Seed Extract on Human Cancer Cell Lines Delivered in Its Native Form and Loaded in Polymeric Micelles

International Journal of Biomaterials ◽

10.1155/2019/9404383 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Watcharaphong Chaemsawang ◽

Weerapong Prasongchean ◽

Konstantinos I. Papadopoulos ◽

Garnpimol Ritthidej ◽

Suchada Sukrong ◽

...

Keyword(s):

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Polymeric Micelles ◽

Cancer Cell Lines ◽

Seed Extract ◽

Abelmoschus Esculentus ◽

Native Form ◽

Flavonoid Compounds ◽

Mcf 7

Cancer is a noncommunicable disease with a high worldwide incidence and mortality rate. The National Cancer Institute of Thailand reports increasing cumulative incidence of breast, colorectal, liver, lung, and cervical cancers, accounting for more than 60% of all cancers in the kingdom. In this current work, we attempt to elucidate the phytochemical composition of the okra (Abelmoschus esculentus (L.) Moench) seed extract (OSE) and study its anticancer activity, delivered in its native form as well as in the form of polymeric micelles with enhanced solubility, in three carcinoma cell lines (MCF-7, HeLa, and HepG2). The presence of flavonoid compounds in the OSE was successfully confirmed, and direct delivery had the highest cytotoxic effect on the breast cancer cell line (MCF-7), followed by the hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cell lines in that order, while its delivery in polymeric micelles further increased this effect only in the HepG2 cell line. The OSE’s observed cytotoxic effects on cancer cell lines demonstrated a dose and time-dependent cell proliferation and migration inhibition plausibly due to VEGF production inhibition, leading to apoptosis and cell death, conceivably due to the four flavonoid compounds noted in the current study, one of which was isoquercitrin. However, in view of the latter compound’s isolated effects being inferior to those observed by the OSE, we hypothesize that either isoquercitrin requires the biological synergy of any one or all of the observed flavonoids or any of the three in isolation or all in concert are responsible. Further studies are required to elucidate the nature of the three unknown compounds. Furthermore, as we encountered significant problems in dissolving the okra seed extract and creating the polymeric micelles, further studies are needed to devise a clinically beneficial delivery and targeting system.

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PRELIMINARY CYTOTOXIC EVALUATION OF Andrographis paniculata IN BREAST CANCER CELL LINES

Jurnal Bioteknologi & Biosains Indonesia (JBBI) ◽

10.29122/jbbi.v2i1.533 ◽

2016 ◽

Vol 2 (1) ◽

pp. 34

Author(s):

Tarwadi . ◽

Churiyah . ◽

Olivia Bunga Pongtuluran ◽

Fifit Juniarti ◽

Fery Azis Wijaya

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Andrographis Paniculata ◽

Normal Fibroblast ◽

Breast Cancer Cell Lines ◽

Mcf 7

Sambiloto (Andrographis paniculata) banyak digunakan untuk mengobati berbagai penyakit di Indonesia dan negara-negara Asia lainnya. Dalam studi ini, ekstrak metanol dan etanol sambiloto yang diperoleh dari B2PTO Tawangmangu telah diuji terhadap sel lini kanker payudara T47D dan MCF-7 dan sel lini normal fibroblast HFL-1 menggunakan reaksi enzimatik 3-(4,5-dimethylthiazoyl-2-yl) 2,5-diphenyltetrazoliumbromide (MTT). Uji in vitro terhadap sel lini normal fibroblast HFL-1 menunjukkan bahwa 50 ppm ekstrak metanol sambiloto tidak menghambat pertumbuhan sel. Tetapi, ekstrak metanol dan etanolnya menghasilkan IC50 yang relatif rendah pada sel lini kanker payudara, yaitu 111 ppm dan 122 ppm pada sel lini MCF-7 dan 70 ppm dan 197 ppm pada sel lini T47D. Selain itu, campuran ekstrak sambiloto yang mengandung 25% ekstrak Thyponium divaricatum dan Anredera cordifolia memberikan daya hambat pertumbuhan pada sel kanker payudara MCF-7 yang lebih besar, dengan nilai IC50 masing-masing adalah 68 ppm dan 34 ppm. Kesimpulannya, total ekstrak metanol atau etanol sambiloto yang diperoleh dari Tawangmangu memiliki potensi sebagai sumber senyawa anti-kanker serta perlu kajian lebih lanjut.Kata kunci: Ekstrak Andrographis paniculata, MTT, sel lini normal, sel lini kanker, aktivitas anti kanker ABSTRACTSambiloto (Andrographis paniculata) is widely used as medicine to treat various diseases in Indonesia and other Asian countries. In this study, methanolic and ethanolic extracts of sambiloto collected from B2PTO Tawangmangu have been tested againts breast cancer cell lines of T47D and MCF-7 and normal fibroblast cell line of HFL-1 using enzymatic reaction of 3-(4,5-dimethylthiazoyl-2-yl) 2,5-diphenyltetrazoliumbromide (MTT). In vitro assay performed on normal fibroblast of HFL-1 cell line showed that 50 ppm of methanolic extract of sambiloto did not inhibit cell growth. However, methanolic and ethanolic extracts of sambiloto gave relatively low of IC50 on breast cancer cell lines which were 111 ppm and 122 ppm on the MCF-7 cell lines and 70 ppm and 197 ppm on the T47D cell lines, respectively. In addition, the mixture of sambiloto extract containing 25% of Thyponium divaricatum and Anredera cordifolia extracts confered greater growth inhibition on breast cancer cell line of MCF-7, where IC50 values were 68 ppm and 34 ppm, respectively. In conclusion, the total methanolic or ethanolic extract of sambiloto collected from Tawangmangu has potency as a source of anti-cancer compounds and needs further study.Key words: Andrographis paniculata extract, MTT, normal cell line, cancer cell lines, anti-cancer activity

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