Abstract
The indolo[2,3-a]carbazole alkaloids constitute an important class of natural products with interesting and diverse biological activities. A series of novel ring-fused indolocarbazoles were synthesized and evaluated for inhibition of topoisomerase I-mediated relaxation of supercoiled DNA and in vitro antitumor activity. The derivatives bearing a methylenedioxy or an ethylenedioxy ring fused onto the nonglycosylated indole (1a, 1b) demonstrated more potent anti-topoisomerase I activity. The isopropylenedioxy analogue 1c was approximately half as active as 1a, while the O-dimethoxy analogue 1d and the regioisomers 2a and 2b were essentially devoid of measurable activity, implying that the stacking with the intact DNA strand has been impeded by these compounds due to steric hindrance. The newly synthesized indolocarbazoles were screened against the NCI’s 60 tumor cell lines. The order of activity, based on the mean GI50 values, is as follows: 1a > 2a ~ 1d > 1b > MCR-47 > 2b. Though in general the analogues that showed potent activity against topoisomerase I (1a, 1b) also showed potent in vitro inhibition of tumor cell growth, the antitumor activity of the anti-topoisomerase I inactive 1d and 2a were intriguing. COMPARE analyses confirmed that the topoisomerase I is the primary target for 1a and 1b; however, other target(s) or pathway(s) may also be involved, with PLD1 and MERTK suggested. Further investigation of these molecular targets against these indolocarbazoles is warranted.
Keywords: Antitumor, COMPARE analysis, GI50, LC50, Methylenedioxy- and ethylenedioxy-fused indolocarbazole, NCI 60 tumor cell lines, Synthesis, TGI, Topoisomerase I inhibitor, Ethylenedioxyindole
Anti-Cancer Agents in Medicinal Chemistry
Title:Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles: Potent Human Topoisomerase I Inhibitors and Antitumor Agents
Volume: 12 Issue: 9
Author(s): David E. Zembower, Yongping Xie, Ali Koohang, Mary J. Kuffel, Matthew M. Ames, Yasheen Zhou, Rama Mishra, Aye Aye Mar, Michael T. Flavin and Ze-Qi Xu
Affiliation:
Keywords: Antitumor, COMPARE analysis, GI50, LC50, Methylenedioxy- and ethylenedioxy-fused indolocarbazole, NCI 60 tumor cell lines, Synthesis, TGI, Topoisomerase I inhibitor, Ethylenedioxyindole
Abstract: The indolo[2,3-a]carbazole alkaloids constitute an important class of natural products with interesting and diverse biological activities. A series of novel ring-fused indolocarbazoles were synthesized and evaluated for inhibition of topoisomerase I-mediated relaxation of supercoiled DNA and in vitro antitumor activity. The derivatives bearing a methylenedioxy or an ethylenedioxy ring fused onto the nonglycosylated indole (1a, 1b) demonstrated more potent anti-topoisomerase I activity. The isopropylenedioxy analogue 1c was approximately half as active as 1a, while the O-dimethoxy analogue 1d and the regioisomers 2a and 2b were essentially devoid of measurable activity, implying that the stacking with the intact DNA strand has been impeded by these compounds due to steric hindrance. The newly synthesized indolocarbazoles were screened against the NCI’s 60 tumor cell lines. The order of activity, based on the mean GI50 values, is as follows: 1a > 2a ~ 1d > 1b > MCR-47 > 2b. Though in general the analogues that showed potent activity against topoisomerase I (1a, 1b) also showed potent in vitro inhibition of tumor cell growth, the antitumor activity of the anti-topoisomerase I inactive 1d and 2a were intriguing. COMPARE analyses confirmed that the topoisomerase I is the primary target for 1a and 1b; however, other target(s) or pathway(s) may also be involved, with PLD1 and MERTK suggested. Further investigation of these molecular targets against these indolocarbazoles is warranted.
Export Options
About this article
Cite this article as:
E. Zembower David, Xie Yongping, Koohang Ali, J. Kuffel Mary, M. Ames Matthew, Zhou Yasheen, Mishra Rama, Aye Mar Aye, T. Flavin Michael and Xu Ze-Qi, Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles: Potent Human Topoisomerase I Inhibitors and Antitumor Agents, Anti-Cancer Agents in Medicinal Chemistry 2012; 12 (9) . https://dx.doi.org/10.2174/187152012803529628
DOI https://dx.doi.org/10.2174/187152012803529628 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Pyrrolopyrazoles: Synthesis, Evaluation and Pharmacological Screening as Antidepressant Agents
Medicinal Chemistry Dopamine: Agonists and Neurodegenerative Disorders
Current Drug Targets Neuro-Immune-Endocrine Mechanisms During Septic Shock: Role For Nitric Oxide in Vasopressin and Oxytocin Release
Endocrine, Metabolic & Immune Disorders - Drug Targets The Renin-Angiotensin System: The Role of Inhibitors, Blockers, and Genetic Polymorphisms in the Treatment and Prevention of Heart Failure
Current Vascular Pharmacology Elucidation of Abnormal Extracellular Regulated Kinase (ERK) Signaling and Associations with Syndromic and Non-syndromic Autism
Current Drug Targets Drugs and Rhabdomyolysis: From Liver to Kidney
Current Vascular Pharmacology Diabetic Peripheral Neuropathy: Diagnosis and Treatment
Current Drug Safety Diamidine Activity Against Trypanosomes: The State of the Art
Current Molecular Pharmacology The Role of Dietary Fats in Hypertension, Obesity and Insulin Resistance: A Comparative Study of Animals and Humans in Fetal and Adult Life
Current Nutrition & Food Science Targeted Therapies in Head and Neck Cancer: Past, Present and Future
Reviews on Recent Clinical Trials Is Renalase a Novel Player in Catecholaminergic Signaling? The Mystery of the Catalytic Activity of an Intriguing New Flavoenzyme
Current Pharmaceutical Design Antiphospholipid Syndrome as a Neurological Disease
Current Rheumatology Reviews Acute and Sub-acute Oral Toxicity Assessment of a Standardized Polyherbal Preparation POL-6 in Rats
The Natural Products Journal The ACE2-Ang-(1-7)-Mas Axis and Cardioprotection
Current Cardiology Reviews Geriatric Depression - Review for Primary Care
Current Psychiatry Reviews Editorial (Thematic Issue: Medicinal Chemistry from Fungi and Back: Discovery of Novel Anti-Fungal Drugs and Mycotherapy of Cancer and Other Diseases with Fungal Metabolites)
Current Topics in Medicinal Chemistry An Overview of the Effect of Weight Loss on Cardiovascular Autonomic Function
Current Diabetes Reviews Importance of ABC Transporters in Drug Development
Current Pharmaceutical Design Therapeutic Angiogenesis in Ischemic Heart Disease: Gene or Recombinant Vascular Growth Factor Protein Therapy?
Current Gene Therapy Attacking HIV Provirus: Therapeutic Strategies to Disrupt Persistent Infection
Infectious Disorders - Drug Targets