Triazines Hexamethylmelamine And Trimelamol

Hexamethylmelamine (HMM, altretamine) was originally prepared as a resin precursor, but it was studied as an antitumor compound because of its structural analogy with the previously mentioned aziridine derivative TEM. Although it is active in several types of tumors, its main therapeutic role is in the treatment of recurrent ovarian cancer, following first-line treatment with cisplatin. The precise mechanism of altretamine cytotoxicity is unknown, although several proposals have been made. The...

Proteasome Inhibitors

Protein degradation is essential for the cell to supply fresh amino acids for protein synthesis and also to remove unneeded proteins including excess enzymes and transcription factors that are no longer required or damaged. There are primarily two types of cellular structures that are in charge of protein degradation Medicinal Chemistry of Anticancer Drugs 2008 Elsevier B. V. - Lysosomes, which exert their proteolytic function on extracellular proteins from endocytosis and phagocytosis...

Prodrugbased Anticancer Drug Targeting Smallmolecule Prodrugs

One approach that allows improving the selectivity of cytotoxic compounds in cancer therapy is the use of prodrugs that are selectively activated in tumor tissues.1 This selective activation may be based on the exploitation of some unique aspects of tumor physiology, such as selective enzyme expression, hypoxia, and low extracellular pH. Other approaches are based on tumor-specific delivery techniques that allow the selective activation of prodrugs by exogenous enzymes, which are delivered into...

Info

FIGURE 12.13 The base-excision repair process. FIGURE 12.14 Mechanism of the reaction catalyzed by DNA glycosilases. the repair of deaminated or alkylated bases. The hydrolysis is carried out by a hydroxide anion generated by deprotonation of a molecule of water by a Asn or Asp residue (Fig. 12.14).70 Bifunctional glycosylases normally remove bases that have suffered oxidative damage. The catalytic cycle of these enzymes involves an initial SN1-like attack at the C-1' position by Lys or Pro...

F

FIGURE 12.22 Acidification of tumor environments by tumor-associated carbonic anhydrase IX. mechanism of antitumor action and is under clinical development for the treatment of solid tumors (see Section 4.1 of Chapter 9).91 1. Kerr, D., and Middleton, M. (2006). Curr. Opin. Pharmacol. 6, 321. 2. Gottesman, M. M., Fojo, T., and Bates, S. E. (2002). Nat. Rev. Cancer 2,48. 3. Fl gge, U. I., and van Meer, G. (2006). FEBS Lett. 580, 997. 4. Gottesman, M. M., and Ling, V. (2006). FEBS Lett. 580, 998....

Mmmmvimmmm

FIGURE 12.1 Effects of ABC efflux pumps (A) and their blockade (B) on the intracellular concentrations of anticancer drugs. the development of compounds that behave as blockers of the transport protein and hence can restore the sensitivity of the cell to the anticancer drug (Fig. 12.1B). P-gp, a member of the ABCB transporter subfamily, is a membrane-associated 170-kDa glycoprotein that effluxes 50 of all anticancer agents used clinically today without chemically modifying them. It is...

Introduction

Some General Remarks About Cancer and 2. A Brief Account of the Role of Chemistry in 3. Natural Products in Cancer Chemotherapy 5 4. A Brief Comment About Cancer Nanotechnology 6 5. Conclusion 7 References 7 1. SOME GENERAL REMARKS ABOUT CANCER AND CANCER CHEMOTHERAPY Cancer is a collective term used for a group of diseases that are characterized by the loss of control of the growth, division, and spread of a group of cells, leading to a primary tumor that invades and destroys...

Thymidylate synthase

Thymidylate synthase (TS) catalyzes the conversion of deoxyuridine monophosphate (dUMP) to thymidylate (TMP), in a reductive methylation that involves the transfer of a carbon atom from the cofactor 5,10-methylenetetrahydrofolate to the FIGURE 2.12 Feedback inhibition of ribonucleotide reductase. FIGURE 2.12 Feedback inhibition of ribonucleotide reductase. 5 position of the pyrimidine ring. This transformation, that is the only de novo source of thymidylate, is part of the so-called thymidylate...

Nonclassical lipophilic DHFR inhibitors

Suppression of the glutamic chain leads to compounds that are not substrates for the folate active transport systems, and enter the cells by passive diffusion. They have the advantage of being active in cancer cells resistant to MTX because of transport defects. On the contrary, the lack of the glutamic acid side chain prevents polyglutamation and therefore these compounds are not retained within the cells and require more prolonged treatments. Among these compounds, trimetrexate is mainly used...

Qnh2

Bleomycin A2 R HN' Bleomycin B2 R HN' Tallysomycin S10b (TLM S10b) is another member of the bleomycin family that has reached clinical trials in patients with advanced head and neck tumors, showing a response similar to that of bleomycin A2.71 Its high toxicity prompted the development of immunoconjugates for intracellular targeting (see Section 4.5 of Chapter 11). The bleomycins require a reduced transition metal, Fe (II) or perhaps Cu (I), oxygen, and a one-electron reduction to generate an...

V

FIGURE 6.17 Reversibility of the covalent DNA-ET-743 complex. Because of the complexity of the ET-743 structure, extensive studies have been carried out on the preparation of simpler analogues. Among them, the most important is phthalascidin,74 with an activity similar to that of the natural product, where the phthalimino group plays a similar role to the spirotetrahydroisoquino-line unit in ET-743.75 Another related compound is PM00104 50, which has recently begun Phase I clinical trials for...

Modulation of 5FU activity

Great efforts have been made to modulate the activity of 5-FU, which have focused on (1) decreasing its degradation, (2) enhancing its potency as a TS inhibitor, and (3) increasing 5-FU activation. 4.4.1. Decreased degradation of 5-FU More than 80 of administered drug is degraded in the liver by dihydropyrimi-dine dehydrogenase (DPD), which reduces the pyrimidine double bond of 5-FU to give dihydrofluorouracil (DHFU).23 This metabolite is inactive because it cannot give the initial Michael...

Triazenes

Dacarbazine (DTIC) is employed in combination therapy for the treatment of metastatic malignant melanoma and Hodgkin's disease. This compound was initially designed as an antimetabolite since it is an analog of 5-aminoimidazole-4-carbox-amide, an intermediate in purine biosynthesis. However, its cytotoxic activity is due to the generation during its metabolism of methyldiazonium, which methylates DNA.53 Methyldiazonium has a half-life of about 0.4 s in aqueous solution, which is sufficient to...

Gestagens as antitumor agents

Agonists of the gestagen receptor such as megestrol acetate, medroxyprogesterone acetate, and norethisterone acetate are able to induce apoptosis by binding to progesterone receptors in the cell surface. About 80 of endometrial carcinomas and also some types of breast cancers show a positive response to these drugs.

Inhibitors of glycinamide ribonucleotide formyltransferase GARFT

The third reaction in the de novo purine biosynthesis is the transformation of glycinamide ribonucleotide (GAR) into its formylderivative (FGAR) using 10-formyl-THF as the formyl donor (Fig. 2.32). The enzyme that catalyzes this step is known as glycinamide ribonucleotide formyltransferase (GARFT). In mammals, this enzyme is multifunctional and it also catalyzes the second and fifth steps of the pathway. The first selective and sufficiently potent GARFT inhibitor was lometrexol, designed as a...

Folate Based TS inhibitors

As previously mentioned, TS inhibition by the fluoropyrimidines is not specific because of the effect of fluorinated nucleotides on other pathways, especially related to RNA (Figs. 2.15 and 2.18). Also, the accumulated dUMP may compete with the antitumor drug for TS. For this reason, there has been much interest in the design of inhibitors that recognize the folate-binding site of TS, which should not have these shortcomings and thus behave as specific TS inhibitors. Four of them (raltitrexed,...

Drugs That Modulate Resistance to Antitumor Agents

ATP-Binding Cassette Efflux Pumps in Anticancer 1.1. General features of ABC efflux pumps 388 2. Glutathione and Glutathione-S-Transferase in Anticancer 2.1. Inhibitors of glutathione biosynthesis 398 2.2. Inhibitors of glutathione-S-transferase 399 3. Chemosensitizers Targeting DNA-Repair Systems 401 3.1. Inhibitors of O6-alkylguanine-DNA alkyltransferase 403 3.2. Potential antitumor adjuvants targeting the BER process 404 3.3. Inhibitors of enzymes involved in double-strand DNA...

Photodynamic Therapy Of Cancer

Photodynamic therapy (PDT) of cancer is based on the use of compounds that are able to absorb harmless visible light energy and transfer it efficiently to other molecules in their vicinity or alternatively use it for photochemical reactions with biomolecules.100 These compounds are normally known as photosensitizers (PS). After irradiation with light of the suitable wavelength, the PS molecules are excited from the ground state (1PS0) to a singlet excited state (1PS*) that can reverse to the...

Inhibitors Of Heatshock Proteins

Protein folding is catalysed in vivo by isomerases and chaperone proteins. Molecular chaperones are ubiquitous proteins that assist folding, assembly, transport, and degradation of proteins within the cell. The first identified chaperones were heat-shock proteins (HSPs), whose names is derived from the elevated levels produced when cells are grown at higher-than-normal temperatures. HSPs stabilize other proteins during their synthesis and assist in protein folding by binding and releasing...

Enediyne Antibiotics

This family of antitumor antibiotics contains as a common structural feature a macrocyclic ring with a conjugated system containing at least one double and two triple bonds. Some members of the group are neocarzinostatin (zinostatin), the oldest of them, isolated from various microorganisms, the esperamicins calichea-micins, from a Micromonospora echinospora spp. Calichensis, and dynemicin A, from Micromonospora chersina, which combines the structural features of the anthracyclines and the...

GnRh Lhrh antagonists

When administered to patients with prostatic cancer, GnRH antagonists act by direct inhibition of GnRH receptors and therefore LH secretion, leading to a faster onset of the action (hours instead of days) and avoiding the initial rise of testosterone levels induced by GnRH receptor agonists. GnRH antagonists currently in clinical use are peptidomimetics obtained by extensive modification of the natural GnRH hormone. The main problems to be overcome were the tendency of the first compounds to...

Allosteric inhibition of RNR

Therapeutically significant inhibition of RNR can also be achieved through a feedback mechanism by accumulation of deoxyguanosine triphosphate (dGTP) as a consequence of the inhibition of purine nucleoside phosphorylase (PNP), the enzyme that catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides to form purine and a-d-phosphorylated ribosyl products. This inhibition leads to increased blood levels of one of its substrates, deoxyguanosine (dG), which is...

Inhibitors of 5areductase

The androgenic activity in the prostate is due to 5a-dihydrotestosterone (DHT), since 95 of testosterone entering the prostate is converted to the more potent androgen DHT by the 5a-reductase enzyme of the type 2. Hence, blockade of that enzyme, whose expression is largely restricted to the prostate, facilitates the inhibition of testosterone action on urogenital sinus tissue derivatives, notably Pregnenolone 17a-hydroxylase C(17,20)-lyase Cholesterol side-chain cleavage enzyme (CSCC)...

Introduction Radicals And Other Reactive Oxygen Species

A radical (sometimes called free radical) is a chemical species capable of independent existence that contains one or more unpaired electrons. Molecular oxygen is the main promoter of the formation of radicals within the cells because ground state oxygen contains two unpaired electrons, each one in a different p* Medicinal Chemistry of Anticancer Drugs 2008 Elsevier B. V. antibonding orbital, and hence it can be considered as a biradical. Both electrons have the same spin quantum number and...

Anticancer Drugs Acting On Apoptotic Signalling Pathways

Cancer Drugs Pathways

Apoptosis is normally defined as programmed active cell death. Although at first sight cell death might be viewed as a pathological phenomenon, each second about one million cells in a human body undergo apoptosis. Several genes involved in the apoptosis process have been found to be defective in cancer cells, specially the BCL2 and caspase-family genes.123 Apoptosis is caused by a group of cysteine aspartyl specific proteases called caspases, which cleave their substrates at aspartic acid...

Steroidal aromatase inhibitors type I inhibitors

Aromatase inhibitors are normally classified as steroidal (type I) or nonsteroidal (type II). Numerous steroidal agents have been developed that exhibit either competitive inhibition, irreversible inhibition, or mechanism-based inhibition of aromatase.24 Mechanism-based inhibitors are bound to the catalytic site of the enzyme, which transforms them into electrophilic intermediates that become irreversibly attached to the enzyme, blocking its activity, and they are known as ''aromatase...

Antiandrogens

Androgen antagonists37 bind to the receptor and prevent binding of the natural steroids, but they do not produce the correct conformational change in the receptor that is essential to elicit normal changes in gene expression. Cyproterone is a steroidal antiandrogen that was initially developed as a synthetic gestagen to be used as a contraceptive, but the observation of feminization of the offspring in gestating rats led to its identification as a competitive inhibitor of the AR. It is used in...

Compounds Acting On Other Proteins Of The Nuclear Receptor Superfamily Retinoids

Vitamin A and its analogs, collectively known as retinoids, have profound effects in cell growth and differentiation, and the loss of retinoid function is linked to carcinogenesis in some cancers. The diet-derived all-trans retinoic acid is the main retinoid in humans. Several retinoids have shown promising activity as antitumor and cancer chemopreventive agents by inhibiting carcinogenesis at the initiation, promotion, and progression stages.51 The anticancer activity of retinoids is mainly...

Steroidal antiestrogens

Receptor Ligand Binding Johnson

The SERMs, especially tamoxifen and toremifene, have been the preferred first-line hormonal therapy in estrogen-responsive postmenopausal breast cancer, but they have several disadvantages that are related to their partial estrogenic agonistic activity. These include tumor stimulation in some patients at the initial stages of the treatment (tumor flare) and increased hot flashes, endometrial cancer, and thromboembolism. These limitations stimulated the search for pure ER antagonists....

Glucocorticoids and inhibitors of their biosynthesis as antitumor agents

The immunosuppressive and anti-inflammatory activities of the glucocorticoids are well known. They exert an influence in human lymphoid tissue (e.g., they can modify the homing of lymphocytes into lymphoid organs), and for this reason they are often useful in the treatment in acute lymphoblastic leukemia and other chronic and acute leukemias. Prednisone is normally employed for this purpose, normally in association with other types of chemotherapy. Because of their anti-inflammatory action,...

Tributyrin Anticancer

FIGURE 10.18 Biological effects of HDAC inhibitors. Acetylated histone Proton H2O transfer FIGURE 10.19 Proposed mechanism for the reaction catalyzed by Zn2+-dependant HDAC. proteases. Nucleophilic attack of water onto the carbonyl leads to the formation of a tetrahedral intermediate, stabilized by two zinc-oxygen interactions, similar to zinc proteases, and possibly by a hydrogen bond with the Tyr-303 hydroxyl (10.25). In the final step, the tetrahedral intermediate evolves by cleavage of the...

Nonsteroidal antiestrogens SERMs

The discovery of this group of compounds is a good example of serendipity. They are derivatives of the triphenylethylene system, developed by molecular manipulation of diethylstilbestrol, the prototype nonsteroidal estrogen agonist. The key structural features of this group of compounds, which are essential for activity, are the presence of a triphenylethylene core and a basic aminoether side chain at the 4-position of one of the phenyl rings.4 The first discovered antiestrogen was clomiphene,...

Inhibitors of phosphoribosylformylglycinamidine synthetase

Fdg Glucose Analog

This enzyme catalyzes the reaction of formylglycinamide ribonucleotide with ammonia to give formylglycinamidine ribonucleotide, with glutamine as a cofactor. The enzyme activates the amide group adjacent to the ribose ring to nucleophilic attack by its transformation into iminoether 2.28. In addition, another catalytic site of the enzyme hydrolyzes glutamine to glutamic acid and ammonia, which is then channeled to the first site and reacts with 2.28 by an addition-elimination mechanism,...

Aromatase mechanism of action

Aromatase belongs to the group of microsomal cytochrome P450 enzymes responsible for hydroxylation metabolic processes. The overall process catalyzed by aromatase comprises a series of three oxidative steps. The first two are the insertion of two hydroxyl groups at the C-19 methyl group of its substrates leading to 3.9 and then to gem-diol 3.10, which is dehydrated to aldehyde 3.11. The third reaction is only partly understood, and involves loss of the C-19 carbon atom as a molecule of formic...

Anthracyclines And Their Analogs

Anthracycline Semiquinone

Anthracyclines are a group of antibiotics characterized by the presence of a planar chromophore containing an anthraquinone fragment, attached to an amino sugar. Daunomycin or daunorubicin (DNR) and doxorubicin (DOX), previously called adriamycin, were isolated from a Streptomyces species and were the first anthracycline antibiotics introduced in the clinic for cancer treatment. They are widely used for the treatment of human cancers, and, despite its very similar structure, their antitumor...

Chartreusin Elsamicin A And Related Compounds

Chartreusin and elsamicin A are structurally related antibiotics with antitumor activity. These compounds cause single-strand scission of DNA in the presence of reducing agents via the formation of free radicals. ESR spin-trapping experiments showed that the elsamicin A-iron complex produces hydroxyl radicals in the presence of dithiothreitol as reducing agent.67 The most probable mechanism involves reduction of either carbonyl group followed by reoxidation by oxygen (Fig. 4.24). Because...

References

U. (2004). Curr. Cancer Drug Targets 4,313. 2. Dancey, J., and Sausville, E. A. (2003). Nat. Rev. Drug Discov. 2, 296. 3. Collins, I., and Workman, P. (2006). Curr. Signal Transduct. Ther. 1,13. 4. Keri, G., Orfi, L., Eros, D., Hegymegi-Barakonyi, B., Szantai-Kis, C., Horvath, Z., Waczek, F., Marosfalvi, J., Szabadkai, I., Pato, J., Greff, Z., Hafenbradl, D., et al. (2006). Curr. Signal Transduct. Ther. 1, 67. 5. Klein, S., and Levitzki, A. (2006). Curr. Signal...

Nonsteroidal aromatase inhibitors type II

This group of inhibitors comprises structurally varied compounds that are able to bind to the active site of aromatase through the coordination of an heterocyclic nitrogen atom, usually an imidazole or triazole ring, to the iron atom of the heme group of the enzyme. Because of the similarity of aromatase with other essential enzymes of the cytochrome P450 group, the main problem to be solved is one of selectivity. On the contrary, they have the advantage over steroidal inhibitors of not being...

Pyrimidine nucleosides

The main anticancer compounds belonging to this group are cytosine or azacyto-sine nucleosides with a modified ribose ring, including cytarabine (Ara-C), fazarabine, gemcitabine (dFdC), and azacitidine. Among the arabinose-derived nucleosides, cytarabine (Ara-C), the 2'-epimer of cytidine, is useful in several leukemias, including acute myelogenous leukemia and non-Hodgkin lymphoma. Cytarabine is employed either as a single agent or in combination with others, specially the anthracyclines, and...

Steroid Sulfatase Inhibitors

It was previously mentioned that in postmenopausal women, who show the highest incidence of breast cancer, estrogens are produced in adipose tissues and in the breast by the action of aromatase on androstenedione. However, the clinical response to aromatase inhibitors is not as high as expected, and often it is not superior to the one obtained with antiestrogens or with other antihormones. Furthermore, there appears to be no relationship between the clinical response and the degree of...

N No

Nitrosoureas have been widely studied from a mechanistic point of view. The presence of the nitroso group labilizes the nitrogen-carbon bond, leading to two electrophiles, an isocyanate 5.33 and a diazene hydroxide 5.34, which has been detected in some cases by electrospray ionization mass spectroscopy.45 This intermediate in turn generates a diazonium salt 5.3546 (Fig. 5.25). Alkylation seems to be the main reaction responsible for antitumor activity, while carbamoylation takes place primarily...

N

Dna Alkylating Agents

Tallimustine contains a benzoyl nitrogen mustard unit, which acts as an alkylating moiety, attached to the distamycin A framework. This compound exhibits a most striking DNA sequence specificity of alkylation, which has been studied using the combinatorial selection method known as restriction endonu-clease protection, selection, and amplification (REPSA).6 The highest affinity tallimustine binding sites contain one of two sequences, either the expected distamycin hexamer binding sites followed...

CHOh

Topoisomerase I was validated as a target for cancer chemotherapy when it was identified as the sole target of camptothecin (CPT). This compound was isolated in 1966 from the Chinese tree Camptotheca acuminata and its therapeutic development was initially limited by its poor solubility and unacceptable toxicity. The identification of topoisomerase I as its target prompted the search for water-soluble, more active, less toxic analogues. Structure-activity relationship studies showed that...

Androgenrelated Antitumor Agents

Androgens are steroidal hormones that stimulate and control the masculine primary and secondary characteristics. They exert their action by binding to a nuclear receptor called the androgen receptor (AR)36 and the complex acts as a transcription factor, in a similar way to estrogens. The main androgens are testosterone and its reduced metabolite 5a-dihydrotestosterone (DHT), which has a higher affinity for the AR and three- to tenfold greater molar potency than testosterone. Testosterone 5a -...

Malondialdehyde generation and its consequences

Generation Malondialdehyde

Peroxyl radicals 4.2 can also evolve to cyclic endoperoxides by attack onto a neighboring C C double bond in the same chain, as shown in Figure 4.6 for the case of a molecule of arachidonic acid, in a process resembling the one catalyzed by cyclooxygenase. Peroxyl radicals 4.2 may lead to lipid peroxidation, as previously mentioned (Fig. 4.5). Alternatively, they can cyclize to radical 4.4, which then undergoes a new cyclization, coupled with the addition a second oxygen molecule and subsequent...

Anticancer Drugs Targeting Tubulin and Microtubules

Drugs That Inhibit Microtubule Polymerization at High Concentrations 231 2.1. Compounds binding at the Vinca site 231 2.2. Compounds binding at the colchicine site 236 3. Microtubule-Stabilizing Agents Compounds Binding at the 3.3. Miscellaneous marine compounds that bind to 4. Miscellaneous Anticancer Drugs Acting 5. Antivascular Effects of Microtubule-Targeted Agents 245 6. Mitotic Kinesin Inhibitors 246 References 247 Microtubules are filamentous intracellular structures that are responsible...

A nh3 pf 3 h3n n

MISCELLANEOUS ALKYLATING AND ACYLATING ANTITUMOR AGENTS Pipobroman is used for treatment of polycythemias, like polycythemia vera (Vaquez's disease), a relatively rare chronic disease of the blood in which the red cells are increased in number,70 and essential thrombocythemia.71 Pipobroman has a chemical structure close to that of alkylating agents, although its exact mechanism of action has not been demonstrated. Among the many DNA-damaging natural cytotoxins, leinamycin is of particular...

Contents

Some General Remarks About Cancer and Cancer Chemotherapy 1 2. A Brief Account of the Role of Chemistry in Cancer Chemotherapy 3 3. Natural Products in Cancer Chemotherapy 5 4. A Brief Comment About Cancer Nanotechnology 6 5. Conclusion 7 References 7 2. Inhibitors of the Biosynthesis of Uridylic Acid 10 3. Inhibitors of the Biosynthesis of 2'-Deoxyribonucleotides by Ribonucleotide Reductase (RNR) 11 4. Inhibitors of the Biosynthesis of Thymidilic Acid 18 5. Inhibitors of Dihydrofolate...

Aziridines Ethyleneimines

Since the active species involved in DNA alkylation by nitrogen mustards is an aziridinium cation, several aziridine derivatives were also tested as antitumor agents. Electron-releasing substituents raise the aziridine nitrogen pKa and lead to a high concentration of aziridinium cations 5.20, which renders these compounds too reactive to be of therapeutic value. For this reason, the aziridine units are attached to electron-withdrawing groups, which reduce their reactivity as bases but still...

Medicinal Chemistry Of Anticancer Drugs

CARLOS MEN NDEZ Departamento de Qu mica Org nica y Farmac utica Facultad de Farmacia, Universidad Complutense Madrid, Spain Amsterdam Boston Heidelberg Paris San Diego San Francisco London New York Singapore Sydney Radarweg 29, PO Box 211,1000 AE Amsterdam, The Netherlands Linacre House, Jordan Hill, Oxford OX2 8DP, UK Copyright 2008 Elsevier B.V. All rights reserved No part of this publication maybe reproduced, stored in a retrieval system or transmitted in any form or...

Thiopurines and related compounds

Among nonnatural purine derivatives assayed as antitumor agents, 6-mercapto-purine (MP) and 6-thioguanine (TG) are the most active. These compounds are among the oldest cancer chemotherapeutic drugs in clinical use MP is used for lymphoblastic and myeloblastic leukemias, and the more toxic TG is employed for the treatment of acute non-lymphocytic leukemia. 6-Mercaptopurine requires intracellular metabolism by hypoxanthine guanine phosphoribosyl transferase (HGPRT) to be transformed into the...

Mitoxantrone And Related Quinones

Mitoxantrone, an anthraquinone derivative bearing polyamine side chains, can be considered as a partial analog of the anthracyclines including the hydroxyquinone function. This compound was obtained as an analog of ametantrone, which was initially prepared as a ballpoint pen ink, but a routine screening by NCI led to recognition of its antitumor activity. The reasoning that led to its design54 was based on the observation that a large number of antileukemic agents shared a common N-O-O...

Fluorouracil 5FU and floxuridine

Mechanism Action

The main inhibitors of TS are 5-FU and its deoxynucleoside floxuridine (5-FUdR), and these fluoropyrimidines represent the most widely prescribed class of anticancer drugs worldwide.15 In particular, 5-FU is widely used in the treatment of cancers of the aerodigestive tract, breast, head, and neck, and especially in colo-rectal cancers in combination therapies with oxaliplatin and irinotecan.17 Administered as a cream, it is also useful for the treatment of some skin cancers. 5-FU was developed...

Nitrogen Mustards

Chlorambucil Conjugate Solubility

Sulfur mustard (mustard gas, yperite) was used in World War I for chemical warfare because it is an extremely irritant vesicant agent. After the war, it was realized that it also caused systemic effects such as leukopenia, aplasia of the bone marrow, dissolution of lymphoid tissue, and ulceration of the gastrointestinal tract. This suggested a possible role for this compound in cancer treatment, but after an exploratory study it was considered too toxic for systemic use.4 A nitrogen analog of...

1

FIGURE 11.9 Reductive bioactivation of aziridinylquinones. FIGURE 11.9 Reductive bioactivation of aziridinylquinones. FIGURE 11.10 Release of alkylating species through reductive bioactivation of quinones. Nitroaromatic compounds are reduced by several nitroreductases, which are flavoprotein enzymes that catalyze the stepwise addition of up to six electrons, though the major metabolite is normally the hydroxylamine formed by addition of four electrons. In nitroaromatic compounds with suitable...

DNA Intercalators and Topoisomerase Inhibitors

Topoisomerase Test Condition

DNA Intercalation and Its Consequences 200 2. Monofunctional Intercalating Agents 201 2.1. Ellipticine and its analogues 201 2.3. Fused quinoline compounds 204 2.4. Naphthalimides and related compounds 205 2.5. Chartreusin, elsamicin A, and related compounds 206 3. Bifunctional Intercalating Agents 206 4.1. Topoisomerase I mechanism 209 4.2. Topoisomerase II mechanism 209 5. Topoisomerase II Poisons 211 5.1. Acridine derivatives 213 5.2. Anthracyclines and related compounds 213 5.3....

Jn3

R PhCH2 Cemadotin R C CH3 3 Synthadotin Hemiasterlin was originally reported from the South African sponge Hemias-terella minor, although it was soon also isolated from sponges of the genus Cym-bastela, together with the related hemiasterlins A and B. These agents inhibit tubulin assembly and probably bind at the ''peptide binding site'' shared with the dolastatins and cryptophycins.19 Many synthetic analogs of the hemiasterlins have also been developed, and HTI-286 is under clinical trials.20...

Antimetabolites

Inhibitors of the Biosynthesis of Uridylic Acid 10 3. Inhibitors of the Biosynthesis of 2'-Deoxyribonucleotides by Ribonucleotide Reductase RNR 11 3.1. Structure and catalytic cycle of RNR 12 3.2. Radical scavengers as inhibitors of RNR 13 3.3. Substrate analogs as RNR inhibitors 15 3.4. Allosteric inhibition of RNR 18 4. Inhibitors of the Biosynthesis of Thymidilic Acid 18 4.1. Thymidylate synthase 18 4.2. 5-fluorouracil 5-FU and floxuridine 21 4.4. Modulation of 5-FU activity 27 4.5....

Alkylating and Non Alkylating Compounds Interacting with the DNA Minor Groove

Classes Anticancer Drug

Netropsin, Distamycin, and Related Compounds 178 4. Tetrahydroisoquinoline Alkaloids 189 5. Cyclopropylindole Alkylating Agents 193 References 196 Besides non-specific electrostatic interaction with phosphate groups, there are two main ways in which a molecule can bind to DNA in a reversible way a groove-binding interactions, which do not require conformational changes in DNA and usually shows high sequence specificity and b intercalation of planar or quasi-planar aromatic ring systems...

Anticancer Drugs Acting via Radical Species Photosensitizers and Photodynamic Therapy of Cancer

Introduction Radicals and Other Reactive Oxygen Species 93 2. Biological Effects of ROS 95 2.1. Membrane phospholipid peroxidation 95 2.2. Malondialdehyde generation and its consequences 96 2.3. DNA strand cleavage 98 2.4. Oxidation of DNA bases 100 2.5. Formaldehyde generation 102 2.6. ROS as signaling molecules 102 3. Anthracyclines and Their Analogs 102 4. Mitoxantrone and Related Quinones 112 6. Chartreusin, Elsamicin A, and Related Compounds 116 8. Enediyne Antibiotics 122 12....

Methylhydrazines

When a series of N,N'-dialkylhydrazine derivatives that had been prepared as monoaminooxidase MAO inhibitors were routinely submitted to cytotoxicity tests, it was shown that compounds with an N-methyl substituent had anticancer potential. This discovery ultimately led to the development of procarbazine, which was approved for use in combination therapy for advanced Hodgkin's disease. Mechanistically, procarbazine is a unique agent with multiple sites of action that is not cross-resistant with...

Epigenetic Therapy Of Cancer

The initiation and progression of cancer is controlled by both genetic and epige-netic events. The term ''epigenetic'' refers to alterations in gene expression that are not associated with changes in DNA sequence. Unlike genetic alterations, epigenetic aberrations are potentially reversible. The best studied epigenetic alterations are DNA methylation and histone tail modifications, and epigenetic gene silencing by these mechanisms has become an attractive anticancer target.51 The main enzymes...