Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 15, Issue 5, 2015
Volume 15, Issue 5, 2015
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Recent Advances of Natural and Synthetic β-Carbolines as Anticancer Agents
Authors: Mingming Zhang and Dianqing SunCancer is a leading cause of mortality worldwide, being responsible for millions of deaths annually. Therefore, novel cancer chemotherapeutic agents are urgently needed to combat this devastating disease. β - Carboline alkaloids are an important class of natural products and medicinal molecules, which exert their anticancer activities through diverse mechanisms. In this review, we cover recent natural and synthetic β - carbolines with anticancer activity that have been reported in the literature (2010-July 2014), focusing on their chemical structures, anticancer properties, structure-activity relationships, and mechanisms of action.
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Design and Synthesis of Novel Antineoplastic Agents Inspired from Marine Bromopyrrole Alkaloids
Azetidin-2-one, a β -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.
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Synthesis of Novel Amides Based on Acridone Scaffold with Interesting Antineoplastic Activity
In search of novel cytotoxic agents based on acridone scaffold, twenty five derivatives of acridone-2- carboxamide were synthesized and evaluated against a panel of eleven cancer cell lines by using MTT assay. Amides, A5 and A8 (IC50 = 0.3 µM) exhibited good cytotoxicity against MCF7. Compound A22 (IC50 = 4.3 µM) was found to be selectively cytotoxic against cancer cell line MCF7 and KB403. Particularly, promising cytotoxic activities were shown by amides A6 (IC50 = 0.7 µM), A16 (IC50 = 6.3 µM), A8 (IC50 = 0.9 µM ), A21 (IC50 = 1.3 µM), A5 (IC50 = 2.9 µM), A8 (IC50 = 2.8 µM), A14 (IC50 = 0.8 µM), A9 (IC50 = 0.8 µM) and A8 (IC50 = 0.4 µM) against cell lines; PA1, WRL68, CaCO2, TK-10, K-562, PC-3, HOP-92, ECV-304 and UACC-257, respectively. The favorable cytotoxic profile and non-toxicity towards normal human cells displayed by the derivative revealed their potential for further anticancer drug developments.
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Recent Developments Towards Podophyllotoxin Congeners as Potential Apoptosis Inducers
Authors: Ahmed Kamal, Syed Mohammed Ali Hussaini and M. Shaheer MalikPodophyllotoxin, a lignan extracted from rhizomes of Podophyllum species, is a well established lead in the development of new chemical agents for the treatment of cancer. Its semi-synthetic variant, etoposide is an anticancer drug which inhibits DNA topoisomerase II causing cell cycle arrest in the S the phase. Its clinical success and intriguing mode of action made it a much sought after skeleton for the development of better antitumor agents. Modifications were made at several positions of its skeleton with the aim to either improve its potency or to overcome drug resistance. In recent years, the structurally modified podophyllotoxins have been investigated for their apoptosis inducing ability. Although numerous reviews emphasized the occurrence, synthesis and applications of podophyllotoxins, the recent progress towards development of structurally modified podophyllotoxins possessing apoptosis inducing ability has not been previously reviewed. Therefore the present review focuses on the studies carried out in the design and synthesis of new podophyllotoxin derivatives and their evaluation as apoptosis inducers.
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Anticancer Activity of Polyether Ionophore-Salinomycin
Authors: Michał Antoszczak and Adam HuczyńskiSince the discovery of unusual anti-tumor activity of natural polyether antibiotic – Salinomycin, this compound, along with its derivatives, has been intensively studied against different human cancer cells, both in vivo and in vitro. Salinomycin has shown strong inhibition activity against the proliferation process of many different cancer cells, including multi-drug resistance (MDR) cancer cells, as well as cancer stem cells (CSCs), i.e. leukemic stem cells, colon carcinoma stem cells, prostate cancer stem cells and many others. Additionally, the application of Salinomycin has been proved to enhance the anti-cancer effect of radio- and chemotherapy. Preliminary clinical studies have shown tumor regression and only transient acute side effects after application of Salinomycin. Up to now, major efforts have been devoted to elucidate the biological mechanisms of anti-tumor activity of Salinomycin and it is expected that the results may provide new therapeutic strategies based on biological modulation of Salinomycin activity. This review is focused on and describes the possible role of Salinomycin in cancer therapy and gives an overview of its properties.
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Recent Trends of Chalcones Potentialities as Antiproliferative and Antiresistance Agents
More LessChalcones are natural compounds found in plants, fruits and vegetables. This class of compounds has shown many biological activities including antioxidant, antimicrobial, anti-inflammatory, antifungal and antihypertensive, among others. In cancer, it has been reported that chalcones interfere in several points of the signal transduction pathways related to cellular proliferation, angiogenesis, metastasis, apoptosis and the reversal of multidrug resistance. The large number of research articles and patents related to chalcones is already an indication of their importance as a lead class of compounds. This article gathers recent efforts to elucidate the molecular mechanisms of action of chalcones, associated with their anticancer and anti resistance potential.
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Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance
Authors: Subburayan Karthikeyan and Sugeerappa Laxmanappa HotiMultidrug resistance (MDR) in cancer caused due to overexpression of ABC drug transporters is a major problem in modern chemotherapy. Molecular investigations on MDR have revealed that the resistance is due to various transport proteins of the ABC superfamily which include Phosphoglycoprotein (P-gp/MDR1/ ABCB1), multidrug resistance-associated protein-1 (MRP1), and the breast cancer resistance protein (BCRP). They have been characterized functionally and are considered as major players in the development of MDR in cancer cells. These ATP-dependent transporter proteins cause MDR either by decreased uptake of the drug or increased efflux of the drug from the target organelles. Several MDR-reversing agents are being developed and are in various stages of clinical trials. The first three generations of ABC modulators such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 required to be administered in high doses to reverse MDR and were associated with adverse effects. Additionally, these modulators non-selectively inhibit ABC and adversely accumulate chemotherapeutic drugs in brain and kidney. Currently, research has stepped up towards reversing MDR by using natural products which exhibitted potential as chemosensitizers. Globally, there is a rich biodiversity of natural products which can be sourced for developing drugs. These products may provide more lead compounds with superior activity, foremost to the development of more effective therapies for MDR cancer cells. Here, we briefly review the status of natural products for reversing MDR modulators, and discuss the long term goal of MDR strategies in current clinical settings.
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A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents
Authors: Pravin C. Patil, Vijay Satam and Moses LeeThe duocarmycins and CC-1065 are members of a class of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity none of the analogs have passed clinical evaluation. As a result, the intensity in the design, synthesis, and development of novel analogs of the duocarmycins has continued. Accordingly, in this review, which covers a period from the 1990s through the present time, the design and synthesis of duocarmycin SA are described along with the synthesis of novel and highly cytotoxic analogs that lack the chiral center. Examples of achiral analogs of duocarmycin SA described in this review include seco-DUMSA (39 and 40), seco-amino-CBI-TMI (13, Centanamycin), and seco-hydroxy-CBI-TMI (14). In addition, another novel class of biologically active duocarmycin SA analogs that contained the seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) DNA alkylating submit was also designed and synthesized. The synthesis of seco-iso-CFI-TMI (10, Tafuramycin A) and seco-CFQ-TMI (11, Tafuramycin B) is included in this review.
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A Review on the Synthesis and Anti-cancer Activity of 2-substituted Quinolines
Authors: Kaalin Gopaul, Suhas A. Shintre and Neil A. KoorbanallyQuinolines substituted at C-2 on the quinoline scaffold have shown interesting anticancer activity in a number of anticancer assays such as breast (MCF-7, MDA-MB 231), human cervical epithelioid (HeLa), oral squamous cell carcinoma (SAS), human stomach adenocarcinoma (AGS, MKN45), hepatocellular (SKHep, HepG-2, Hep-3B), prostate (PC-3, DU145), lung (A549, H-460), gastric (HGC, MNK-74), leukemia (K562, U937, REH, NALM6, CEM/ADR 5000), colon (Colo-205, HCT 116, SW620, Caco-2, HT29), neuroblastoma (IMR32), CNS (SF-268), oesophageal (EAC) and melanoma (A-375). They have been synthesised by a number of strategies starting with isatin, anilines, nitrobenzenes and benzamides and some even with cyclohexanone and cyclohexa-1,3-diones with ammonium acetate. Many of the synthetic strategies employ the derivatisation of quinoline precursors itself. We review here the synthesis of 145 bioactive anticancer quinolines substituted at the 2-position and their anticancer activity.
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Curcumin as an Adjuvant to Breast Cancer Treatment
Cancer is the second largest leading cause of death worldwide and breast cancer is the most prevailing cause of mortality among all cases of malignant neoplastic disease in adult females. The incidence rate of breast malignant neoplastic disease is predominantly higher in Western women, when compared to women in Asian nations. The definitive reason for this conflict is even unknown, but dietary factors have been conceived to account for approximately 30% of cancers in Western nations. It has been hypothesized that ethnicity, including use of a variety of spices in the food would be a major reason. Among all spices, turmeric (Curcuma longa) has been proven for its better anticancer potential. In this review different molecular mechanisms including cell cycle arrest; G0/G1 and/or G2/M phase cell cycle arrest by up-regulating Cdk inhibitor, p21/WAF/CIPI and p53, inhibition of transcriptional factors; NFΚB, AP-1, TNFα, IL, STAT-3, and PPAR-γ, downstream gene regulation; c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNFα, interleukins and MMP-9, growth factors; bFGF, EGF, GCSF, IL-8, PDGF, TGFα, TNF, VEGF and cell adhesion molecules; fibronectin, vitronectin, and collagen which are involved in angiogenesis and metastasis, alsothe effectiveness of curcumin, when given in combination with chemotherapeutics like cyclophosphamide, doxorubicin, mitomycin etc. in treating breast cancer have been reviewed.
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Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics
Adenosine Monophosphate-Activated Protein Kinase or AMPK is a highly-conserved master-regulator of numerous cellular processes, including: Maintaining cellular-energy homeostasis, modulation of cytoskeletaldynamics, directing cell growth-rates and influencing cell-death pathways. AMPK has recently emerged as a promising molecular target in cancer therapy. In fact, AMPK deficiencies have been shown to enhance cell growth and proliferation, which is consistent with enhancement of tumorigenesis by AMPK-loss. Conversely, activation of AMPK is associated with tumor growth suppression via inhibition of the Mammalian Target of Rapamycin Complex-1 (mTORC1) or the mTOR signal pathway. The scientific communities’ recognition that AMPK-activating compounds possess an anti-neoplastic effect has contributed to a rush of discoveries and developments in AMPK-activating compounds as potential anticancer-drugs. One such example is the class of compounds known as Biguanides, which include Metformin and Phenformin. The current review will showcase natural compounds and their derivatives that activate the AMPK-complex and signaling pathway. In addition, the biology and history of AMPK-signaling and AMPK-activating compounds will be overviewed, their anticancer-roles and mechanisms-of-actions will be discussed, and potential strategies for the development of novel, selective AMPK-activators with enhanced efficacy and reduced toxicity will be proposed.
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Volumes & issues
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Volume 25 (2025)
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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