1,721,172 research outputs found
Arylthioindoles, potent inhibitors of tubulin polymerization: synthesis and molecular modeling studies.
No full text2-Heterocyclyl-3-arylthio-1H-indoles as potent tubulin polymerization inhibitors with improved metabolic stability
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Premio Farmindustria 2007. XVIII Convegno Nazionale della Divisione di Chimica Farmaceutica della Società Chimica Italiana
No full textViolaceina: un pigmento prodotto dal batterio Janthinobacterium lividum ad attività antitumorale
No full textNovel indolyl aryl sulfones (IASs) highly active in vitro against HIV-1 WT and variants carrying NNRTI resistance mutations
No full textAcquired Immunodeficiency Syndrome (AIDS) is a lethal infection caused by a retrovirus, the human immunodeficiency virus (HIV).
Currently employed anti-AIDS drugs are classified into three main families, the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs).
NNRTIs received great attention because of their HIV-1 selectivity, low toxicity and favourable pharmacokinetic properties. Nevertheless first generation of NNRTI agents suffered from a rapid loss of activity following the emergence of single amino acids mutations in the Reverse Transcriptase (RT). Due to this reason they were not useful as standard components of the highly active antiretroviral therapy (HAART) of AIDS. Second generation NNRTIs, such as efavirenz, were active against a broad panel of mutant resistant strains and proved to be effective substitutes of PIs in HAART schedules. Therefore, there is still a need for second generation NNRTIs for clinical use.
Three NNRTIs are commercially available: nevirapine (Viramune®, 1), delavirdine (Rescriptor®, 2) and efavirenz (Sustiva®, 3), but a large number of NNRTIs have been identified. Among them pyrrolobenzothiazepines (PBTDs, 4), pyrryl aryl sulfones (PASs, 5), 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs, 6) and acylamino pyrryl aryl sulfones (APASs, 7) were discovered in our department (Chart 1).
Prolonged HAART treatments lead to the emergence of drug resistant mutant strains. Thus, searches for novel anti-AIDS agents, active also against viral mutants, need.
L-737,126 (8)1 is a sulfonyl indole-2-carboxyamide, discovered by Merck Laboratories, which showed anti-HIV-1 activity at nanomolar concentrations, but it appeared poorly active against HIV-1 strains carrying clinically relevant mutations.
We focused our attention on the synthesis of novel indolyl aryl sulfones (IASs) active on viral mutants variants of clinical relevance.
Structure Activity Relationship (SAR) studies led us to introduce two methyl groups at positions 3 and 5 of L,737-126 benzenesulfonyl moiety. The most interesting compound of the IAS series (compound 9) showed selectivity and activity at nanomolar concentrations on WT, Y181C, K103N-Y181C and K103-V179D-P225H mutant strains.2
The modulation of the 2-carboxyamide chain led to synthesize 5-chloro-3-arylsulfonyl-1H-indole-2-carboxyamides bearing in sequence one, two or three aminoacids units. Transformation of chain end into amide or hydrazide produced IAS derivatives with potent and selective activity against HIV-1 WT and NNRTI resistant mutants. The glycinyl-glycine carboxyamide was active against the WT strain at EC50 = 0.7 nM; the alanine carboxyamide resulted the most active compound against the double (K103N-Y181C) and triple (K103R-V179D-P225H) mutants. IAS derivatives with N-(2-heterocycloethyl)- or N-(2-arylethyl)-2-carboxyamide portion were found also highly selective and active at nanomolar concentration against some resistant mutants (Chart 2).
The interesting biological profile displayed by the new indolyl aryl sulfones encourage us in further investigations.
Synthesis of IASs. Ethyl or methyl 3-arylthio-5-chloro-1H-indole-2-carboxylates were prepared by reaction of proper N-(arylthio)succinimide with ethyl or methyl 5-chloro-1H-indole-2-carboxylates in the presence of boron trifluoride diethyl etherate. Oxidation of 3-arylthio-1H-indole-2-carboxylates to the related sulfones was performed with 3-chloroperoxybenzoic acid. The hydrolysis of the 3-arylsulfonyl-5-chloro-1H-indole-2-carboxylates with lithium hydroxide furnished the corresponding acids, which were condensed with ethyl or methyl esters of D,L-aminoacids in the presence of BOP and triethylamine. Dipeptide or tripeptide derivatives were prepared under same reaction conditions. The corresponding amides and hydrazides were synthesized reacting the esters with ammonium hydroxide or hydrazine respectively.
References
(1) Williams, T. M.; Ciccarone, T. M.; Mactough, S. C. Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.; Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’ Brien, J. A.; Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.; Anderson, P. S. 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: a novel non-nucleoside reverse transcriptase inhibitor. J. Med. Chem. 1993, 36, 1291-1294.
(2) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; La Colla, P. Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance mutations: synthesis and SAR studies. J. Med. Chem. 2003, 46, 2482-2493
Targeting CBP and p300: Emerging Anticancer Agents
Full text linkCBP and p300 are versatile transcriptional co-activators that play essential roles in regulating a wide range of signaling pathways, including Wnt/beta-catenin, p53, and HIF-1 alpha. These co-activators influence various cellular processes such as proliferation, differentiation, apoptosis, and response to hypoxia, making them pivotal in normal physiology and disease progression. The Wnt/beta-catenin signaling pathway, in particular, is crucial for cellular proliferation, differentiation, tissue homeostasis, and embryogenesis. Aberrant activation of this pathway is often associated with several types of cancer, such as colorectal tumor, prostate cancer, pancreatic and hepatocellular carcinomas. In recent years, significant efforts have been directed toward identifying and developing small molecules as novel anticancer agents capable of specifically inhibiting the interaction between beta-catenin and the transcriptional co-activators CBP and p300, which are required for Wnt target gene expression and are consequently involved in the regulation of tumor cell proliferation, migration, and invasion. This review summarizes the most significant and original research articles published from 2010 to date, found by means of a PubMed search, highlighting recent advancements in developing both specific and non-specific inhibitors of CBP/beta-catenin and p300/beta-catenin interactions. For a more comprehensive view, we have also explored the therapeutic potential of CBP/p300 bromodomain and histone acetyltransferase inhibitors in disrupting the transcriptional activation of genes involved in various signaling pathways related to cancer progression. By focusing on these therapeutic strategies, this review aims to offer a detailed overview of recent approaches in cancer treatment that selectively target CBP and p300, with particular emphasis on their roles in Wnt/beta-catenin-driven oncogenesis
Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy
Full text linkAlterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment
An improved synthesis of ethyl 5-chloro-4-fluoro-1H-indole-2-carboxylate
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