Acridine inhibitors

Heald RA, Stevens MF (2003) Antitumour polycyclic acridines. Palladium(O) mediated syntheses of quino [4,3,2-kl] acridines bearing peripheral substituents as potential telomere maintenance inhibitors. Org Biomol Chem l(19) 3377-3389... 

Examples of acridin alkaloids used in therapeutics as antineoplastic agents is amsacrine (Amsa P-D ), which is used for the treatment of acute leukemia in adults and malignant lymphomas, refractory to conventional therapy. Amsacrin is an intercalating agent and topoisomerase II inhibitor. 

Using specific fluorescent transport substrates, inhibitors and kinetic analysis Using fluorescent xenobiotics or fluorescent analogue of xenobiotics Using special fluorescent xenobiotics or fluorescent analogues of xenobiotics Vital tests with acridine orange or neutral red Metachromatic fluorescence of intercalated or bound acridine orange, 590/530 nm microfluorometry... 

The major class of topoisomerase I inhibitors comprise of the camptothecins, while topoisomerase II inhibitors fall into several classes - anthracyclines (e.g. doxorubicin), anthracenediones (mitoxantrone), anthrapyrazoles (bianthrazole), actinomycins (actinomycin D), acridines (m-AMSA), ellipticines (9-hydroxy-ellipticine) and epidophyllotoxins (Etoposide (VP-16) and VM-26). The chemical... 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Chemical Class Cholinesterase inhibitor monoamine acridine derivative Clinical Pharmacology ... 

Treatment with cholinesterase inhibitors [e.g., physostigmine, amino-acridines)... 

The devastating mental deterioration that characterizes Alzheimer s disease has been attributed to a mishandling of the neurotransmitter acetylchohne. Inhibitors of acetylcholinesterase, the enzyme that catabolizes that substance, would be expected to help restore deficient acetylcholine levels. Several partly reduced acridines have shown some activity in treating Alzheimer s disease. At least one of these, tacrine (14-5), is now approved for use in patients. The initial step in the synthesis of the first of these consists of the sodium amide catalyzed condensation of isatin (14-1) with cyclohexanone. The reaction can be visualized by assuming the first step to involve an attack of amide on isatin to give an amido-amide such as (14-2) (note that no attempt has been made to account for charges). This can then react with... 

In a similar approach, Pimmg and Chen [3] prepared an indexed library of 54 carbamates from a set of nine alcohols and nine isocyanates. The library was prepared as 15 sublibraries in which each of the alcohols and isocyanates was reacted with an equimolar mixture of the other reactants. The product mixtures were tested as inhibitors of acetylcholinesterase and their activities were used as indices to the rows and columns of a two-dimensional matrix reflecting the activities of individual products. An identical approach was used by the same authors in the preparation of a library of 72 tetrahydro-acridines by the condensation of 12 cyclohexanones with six cyanoanilines in 18 sublibraries [4]. 

Actinomycin D is a commonly used inhibitor of both DNA and RNA synthesis. Its planar structure binds noncovalently between the stacked base pairs of duplex DNA this is called intercalation. In this situation the DNA functions as a poor template. Compounds that bind in a similar way include acridine and ethidium. These affect the fidelity of DNA replication. 

Acridines are also known therapeutic agent as inhibitors of monoamine oxidases, NADH-dehydrogenases etc. [151, 152]. Numerous studies regarding these applications have been described [153, 154]. Therefore, the synthesis of new tetracyclic acridine compounds has increased rapidly in the last few years. 

Heterodisulfide (CoM-S-S-HTP) reduction - coupled to primary translocation. The reaction in which ATP is synthesized during methanol reduction to CH4 could be identified with energetically competent membrane vesicles of the methanogenic strain G61. These vesicles, which are orientated more than 90% inside-out, catalyzed CH4 formation from CH3-S-C0M by reduction with H2 (Reactions 7,8) and coupled this process with the synthesis of ATP [112]. CH3-S-C0M reduction generated a ApH (inside acidic) as monitored by acridine dye quenching protonophores and ATP synthase inhibitors exerted their effects in accordance with a chemiosmotic type of ATP synthesis [113],... 

Another dual inhibitor of topoisomerase I and topoisomerase II is XR 5000 (N-2-[(dimethylamino)ethyl]acri-acridine-4-carboxamine). Its cytotoxicity was not affected by the presence of P-glycoprotein, and it seems to be a promising candidate, even in highly resistant tumor cells. However, neither complete nor partial remission was observed during a phase II trial in 20 patients with advanced or metastatic colorectal cancer (21). 

A variety of inhibitors bind to DNA and thereby eliminate its template activity. Notable among these are the intercalating agents, which slip in between base pairs (e.g., the acridines, phenanthridium derivatives), and the an-thracyclines (daunorubicin, doxorubicin, and plicamycin). 

Heterocycle-fused acridines possess a variety of biological activities, including Ca releasing, antiviral (e.g., anti-HIV), antimicrobial (e.g., anti-amebic and antiplasmodium) and antitumor properties. They are also enzyme inhibitors (e.g., topoisomerase II inhibitors and protein tyrosine kinase inhibitors) and have DNA-intercalation and metal-chelating properties. 

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