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Indole And Topoisomerase

Yao-Yao Zheng, Nan-Xing Shen, Zhao-Yang Liang, Li Shen, Min Chen, Chang-Yun Wang
A new prenylated indole alkaloid, named paraherquamide J (1), together with four known compounds (2-5), were isolated from the mangrove rhizosphere soil-derived fungus Penicillium janthinellum HK1-6. The planar structure and relative configuration of 1 were determined by detailed analysis of the spectroscopic data especially the NOESY spectrum. The absolute configuration of 1 was determined by ECD spectra. Compound 2 was first isolated as a natural product and named as paraherquamide K. All isolated metabolites were evaluated for their antibacterial, topoisomerase I (topo I) inhibitory activities and lethality towards brine shrimp Artemia salina...
January 9, 2019: Natural Product Research
Pauline Fagundes Rosales, Flavio Ferreira Marinho, Adriana Gower, Marilda Chiarello, Bianca Canci, Mariana Roesch-Ely, Favero Reisdorfer Paula, Sidnei Moura
Active plant metabolites have been used as prototype drugs. In this context, Tabernaemontana catharinensis (Apocynaceae) has been highlighted because of the presence of active indole alkaloids. Thus, this study aims the bio-guided search of T. catharinensis cytotoxic alkaloids. The chemical composition was identified by high-resolution mass spectrometry, and fractionation was performed by open column and preparative thin-layer chromatography, from plant stems. The enriched fractions were tested in vitro in tumour cells A375 (melanoma cell line) and A549 (adenocarcinomic human alveolar basal epithelial cells), and non-tumour Vero cells (African green monkey kidney epithelial cells)...
December 15, 2018: Bioorganic Chemistry
Tsutomu Fukuda, Yusuke Nanjo, Masahiro Fujimoto, Kenyu Yoshida, Yuko Natsui, Fumito Ishibashi, Fumiyasu Okazaki, Hideto To, Masatomo Iwao
A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions...
November 28, 2018: Bioorganic & Medicinal Chemistry
Giuseppina Sanna, Silvia Madeddu, Gabriele Giliberti, Sandra Piras, Marta Struga, Małgorzata Wrzosek, Grażyna Kubiak-Tomaszewska, Anna E Koziol, Oleksandra Savchenko, Tadeusz Lis, Joanna Stefanska, Piotr Tomaszewski, Michał Skrzycki, Daniel Szulczyk
A series of 2-(1 H -indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1 H -indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains...
October 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
David H McGarry, Ian R Cooper, Rolf Walker, Catherine E Warrilow, Mark Pichowicz, Andrew J Ratcliffe, Anne-Marie Salisbury, Victoria J Savage, Emmanuel Moyo, John Maclean, Andrew Smith, Cédric Charrier, Neil R Stokes, David M Lindsay, William J Kerr
According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases...
September 15, 2018: Bioorganic & Medicinal Chemistry Letters
T P Sajitha, B L Manjunatha, R Siva, Navdeep Gogna, Kavita Dorai, G Ravikanth, R Uma Shaanker
Camptothecin (CPT), a monoterpene indole alkaloid, is a potent inhibitor of eukaryotic topoisomerase I (Top 1). Because of this property, several derivatives of CPT are widely used as chemotherapeutic agents. The compound is produced by several plant species, including Nothapodytes nimmoniana (Family: Icacinaceae) presumably as a deterrent to insect pests. Here, we report, a lepidopteran larva, Lymantria sp. of Lymantriidae family which feeds voraciously on the leaves of N. nimmoniana, without any adverse consequences...
June 2018: Journal of Chemical Ecology
Magdy A H Zahran, Bishoy El-Aarag, Ahmed B M Mehany, Amany Belal, Ali S Younes
A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53-67% of erythromycin activity on the tested bacteria and 60-70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF-7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad-spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11, which showed good activity toward all the tested cell lines except for MCF-7...
May 2018: Archiv der Pharmazie
Sakineh Dadashpour, Saeed Emami
The indole scaffold is one of the most widespread heterocycles in the naturally occurring and synthetic bioactive compounds including anticancer agents. Due to its biodiversity and versatility, it has been a highly privileged motif for the target-based design and development of anticancer agents. In the last decade, many researchers have reported various indole-based compounds with distinct mechanisms involved in producing potential anticancer activities, indicating the importance of indole motif in the anticancer drug development...
April 25, 2018: European Journal of Medicinal Chemistry
Yunrui Cai, Huajian Zhu, Zaccary Alperstein, Wenjun Yu, Artem Cherkasov, Hongbin Zou
Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and they have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved topoisomerase I (Top1) inhibitors. The enzyme strictosidine synthase, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities...
December 15, 2017: ACS Chemical Biology
Elizabeth Almeida Lafayette, Sinara Mônica Vitalino de Almeida, Renata Virginia Cavalcanti Santos, Jamerson Ferreira de Oliveira, Cezar Augusto da Cruz Amorim, Rosali Maria Ferreira da Silva, Maira Galdino da Rocha Pitta, Ivan da Rocha Pitta, Ricardo Olimpio de Moura, Luiz Bezerra de Carvalho Júnior, Moacyr Jesus Barreto de Melo Rêgo, Maria do Carmo Alves de Lima
Molecules bearing indole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated both to DNA and protein interactions. This study focused on the synthesis of new indole derivatives with thiazolidines and imidazolidine rings condensed as side chains as well as the evaluation of their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized and their structures were elucidated by mass spectrometry (MS), infrared (IR), spectroscopy (1)H NMR, (13)C NMR, COSY (1)H-(1)H and HSQC (1)H-(13)C...
August 18, 2017: European Journal of Medicinal Chemistry
Jamerson Ferreira de Oliveira, Talitha Santos Lima, Débora Barbosa Vendramini-Costa, Sybelle Christianne Batista de Lacerda Pedrosa, Elizabeth Almeida Lafayette, Rosali Maria Ferreira da Silva, Sinara Monica Vitalino de Almeida, Ricardo Olímpio de Moura, Ana Lúcia Tasca Gois Ruiz, João Ernesto de Carvalho, Maria do Carmo Alves de Lima
In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI50 values ranging between 1...
August 18, 2017: European Journal of Medicinal Chemistry
Marta Szumilak, Malgorzata Galdyszynska, Kamila Dominska, Irena I Bak-Sypien, Anna Merecz-Sadowska, Andrzej Stanczak, Boleslaw T Karwowski, Agnieszka W Piastowska-Ciesielska
Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs...
May 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Somenath Roy Chowdhury, Ashish Kumar, Joseane Lima Prado Godinho, Sara Teixeira De Macedo Silva, Aline Araujo Zuma, Sourav Saha, Neha Kumari, Juliany Cola Fernandes Rodrigues, Shyam Sundar, Jean-Claude Dujardin, Syamal Roy, Wanderley De Souza, Sibabrata Mukhopadhyay, Hemanta K Majumder
Indole alkaloids possess a large spectrum of biological activities including anti-protozoal action. Here we report for the first time that voacamine, isolated from the plant Tabernaemontana coronaria, is an antiprotozoal agent effective against a large array of trypanosomatid parasites including Indian strain of Leishmania donovani and Brazilian strains of Leishmania amazonensis and Trypanosoma cruzi. It inhibits the relaxation activity of topoisomerase IB of L. donovani (LdTop1B) and stabilizes the cleavable complex...
August 15, 2017: Biochemical Pharmacology
Pilar Manuel-Manresa, Luís Korrodi-Gregório, Elsa Hernando, Alberto Villanueva, David Martínez-García, Ananda M Rodilla, Ricard Ramos, Margarida Fardilha, Juan Moya, Roberto Quesada, Vanessa Soto-Cerrato, Ricardo Pérez-Tomás
Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells...
July 2017: Molecular Cancer Therapeutics
Sue-Ming Chang, Wilson Christian, Ming-Hsi Wu, Tai-Lin Chen, Yi-Wen Lin, Ching-Shu Suen, Hima Bindu Pidugu, Dilip Detroja, Anamik Shah, Ming-Jing Hwang, Tsann-Long Su, Te-Chang Lee
A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking...
February 15, 2017: European Journal of Medicinal Chemistry
Harish C Pal, Santosh K Katiyar
Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non-melanoma skin cancer cells (NMSCC) and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II) compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2...
December 21, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Chong Zhang, Yan Qu, Bingxuan Niu
A series of novel lapachol derivatives possessing indole scaffolds was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in Eca109 and Hela cell lines. Almost all the tested compounds showed manifested potent inhibitory activity against the two tested cancer cell lines. Topo I-mediated DNA relaxation activity indicated that these novel compounds have potent Topoisomerase I inhibition activity. The most potent compounds 4n and 4k demonstrated more cytotoxicity than camptothecin and was comparable to camptothecin in inhibitory activities on Topoisomerase I in our biological assay...
November 15, 2016: Bioorganic & Medicinal Chemistry
Jawaid Akhtar, Ahsan Ahmed Khan, Zulphikar Ali, Rafi Haider, M Shahar Yar
The present review article offers a detailed account of the design strategies employed for the synthesis of nitrogen-containing anticancer agents. The results of different studies describe the N-heterocyclic ring system is a core structure in many synthetic compounds exhibiting a broad range of biological activities. Benzimidazole, benzothiazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, triazoles, quinolines and quinazolines including others drugs containing pyridazine, pyridine and pyrimidines are covered...
January 5, 2017: European Journal of Medicinal Chemistry
Mary Snow Setzer, Javad Sharifi-Rad, William N Setzer
Recently, the emergence and spread of pathogenic bacterial resistance to many antibiotics (multidrug-resistant strains) have been increasing throughout the world. This phenomenon is of great concern and there is a need to find alternative chemotherapeutic agents to combat these antibiotic-resistant microorganisms. Higher plants may serve as a resource for new antimicrobials to replace or augment current therapeutic options. In this work, we have carried out a molecular docking study of a total of 561 antibacterial phytochemicals listed in the Dictionary of Natural Products, including 77 alkaloids (17 indole alkaloids, 27 isoquinoline alkaloids, 4 steroidal alkaloids, and 28 miscellaneous alkaloids), 99 terpenoids (5 monoterpenoids, 31 sesquiterpenoids, 52 diterpenoids, and 11 triterpenoids), 309 polyphenolics (87 flavonoids, 25 chalcones, 41 isoflavonoids, 5 neoflavonoids, 12 pterocarpans, 10 chromones, 7 condensed tannins, 11 coumarins, 30 stilbenoids, 2 lignans, 5 phenylpropanoids, 13 xanthones, 5 hydrolyzable tannins, and 56 miscellaneous phenolics), 30 quinones, and 46 miscellaneous phytochemicals, with six bacterial protein targets (peptide deformylase, DNA gyrase/topoisomerase IV, UDP-galactose mutase, protein tyrosine phosphatase, cytochrome P450 CYP121, and NAD⁺-dependent DNA ligase)...
September 12, 2016: Antibiotics
Sourav Saha, Chiranjit Acharya, Uttam Pal, Somenath Roy Chowdhury, Kahini Sarkar, Nakul C Maiti, Parasuraman Jaisankar, Hemanta K Majumder
Visceral leishmaniasis is a fatal parasitic disease, and there is an emergent need for development of effective drugs against this neglected tropical disease. We report here the development of a novel spirooxindole derivative, N-benzyl-2,2'α-3,3',5',6',7',7α,α'-octahydro-2methoxycarbonyl-spiro[indole-3,3'-pyrrolizidine]-2-one (compound 4c), which inhibits Leishmania donovani topoisomerase IB (LdTopIB) and kills the wild type as well as drug-resistant parasite strains. This compound inhibits catalytic activity of LdTopIB in a competitive manner...
October 2016: Antimicrobial Agents and Chemotherapy
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