Vvu

Aclarubicin (aclacinomycin A), 110, 212, 215, 219 Aconitase, 105 Acridines, as intercalating agents, 206 Actinomycin D (dactinomycin), 114-115, 204 Activated bleomycin, 118 Acute promyelocytic leukemia (APL), 87 Adenosine deaminase inhibitors, 42 ADEPT, 352,355, 364-367,377 Adiol, 74 ADI-PEG, 20 (see PEG-recombinant arginine deiminase) Adozelesin, 194 ADR-925, 106 Adrenocortical cancer, 85 Adriamycin, (see doxorubicin) AEW-541, 265 Aflatoxin B1, 426 AG-014699, 409 AG-2037, 38 AGT inhibitors,...

H

FIGURE 2.23 Approaches to a decreased degradation of 5-FU. 5-FU prodrug ftorafur.24 Alternatively, the coadministration of 5-FU with DPD inhibitors, such as 5-chloro-2,4-dihydroxypyridine (CDHP, gimestat) and enilur-acil (5-ethynyluracil),25 is being investigated, as well as the use of the UFT combination plus DPD inhibitors.26 Eniluracil has received FDA orphan drug designation for its use in combination with fluoropyrimidines in the treatment of hepatocellular cancer. 4.4.2. Enhancement of...

Brief Account Of The Role Of Chemistry In Cancer Chemotherapy

Chemistry has had varying roles in the discovery and development of anticancer drugs since the beginning of cancer therapies.13 In its early history, chemical modification of sulfur mustard gas led to the serendipitous discovery of the still clinically useful nitrogen mustards. Since those years, synthetic chemistry has been extensively used to modify drug leads, especially those of natural origin, and to solve the problem of the often scarce supply of natural products by developing...

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...

Zd 9331

Raltitrexed (TOM) was the first specific TS inhibitor to be approved for clinical use, and it is employed for advanced colorectal cancer. Its structure contains two classical bioisosteric modifications, namely replacement of the pteridine ring of folate by a quinazoline unit and replacement of the benzene ring of folate by a thiophene. This drug is transported into the cells by the reduced folate carrier (RFC), and its terminal glutamate residue is converted into a polyglutamate by...

Aromatase Inhibitors

An alternative strategy for achieving antiestrogenic effects is the inhibition of aromatase, the enzyme responsible for the biosynthesis of estradiol and estrone from androgens.18 In principle, this strategy has the advantage over the use of antiestrogens of blocking the two pathways involved in the generation of tumors by the estrogenic hormones, which were discussed in Section 2, namely ER activation and the generation of carcinogenic metabolites (Fig. 3.13). Aromatase catalyzes the loss of...

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...

Introduction

Anticancer drugs that target DNA have been used in the clinic for more than 60 years.1 Despite the recent major advances in cancer research, the mechanism by which most clinically relevant anticancer drugs kill cells consists of interference with replication, which can be achieved most simply by DNA alkylation. Alkylat-ing agents can be defined as compounds capable of covalently binding an alkyl group to a biomolecule under physiological conditions (aqueous solution, 37 C, pH 7.4). DNA...

Ddp Anticancer Drugs

FIGURE 3.10 Mechanism of action of fulvestrant. FIGURE 3.11 Binding of fulvestrant to the estrogen receptor. Comparison with estradiol binding. FIGURE 3.11 Binding of fulvestrant to the estrogen receptor. Comparison with estradiol binding. binds to the ER which in the resting state has a single domain, called activating function (AF1), available for binding with coactivators and or corepressors. After binding of estradiol, a second activating function (AF2) is exposed. The complex dimerizes and...

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....

Anticancer Drugs That Inhibit Hormone Action

Estrogens and Their Involvement in Carcinogenesis 54 3. Antiestrogens as Antitumor Drugs 58 3.1. Nonsteroidal antiestrogens (SERMs) 58 3.2. Steroidal antiestrogens 62 4. Aromatase Inhibitors 65 4.1. Aromatase mechanism of action 67 4.2. Steroidal aromatase inhibitors (type I inhibitors) 68 4.3. Nonsteroidal aromatase inhibitors (type II) 72 5. Steroid Sulfatase Inhibitors 73 6. Androgen-Related Antitumor Agents 75 6.2. Inhibitors of 14a-demethylase and 17a-hydroxylase 77 6.3. Inhibitors of...

Cep7055

Other types of anti-VEGF therapy Bevacizumab is a recombinant humanized monoclonal IgG1 antibody against all isoforms of VEGF-A, which are ligands of the VEGFR-1 and VEGFR-2. Bevacizu-mab was the first approved agent to inhibit tumor angiogenesis, in 2004 by the FDA and in 2005 in Europe. It is used in combination with other drugs such as 5-fluorouracil or irinotecan for the first-line treatment of patients with metastatic colorectal cancer, and is expected to be approved for other...

References From Anticancer Drugs

M. (2002). Leukemia 26, 433. 2. Neefjes, J., and Dantuma, M. P. (2004). Nat. Rev. Drug Discov. 3, 58. 3. Adams, J. (2004). Nat. Rev. Cancer 4, 349. 4. Myung, J., Kim, K. B., and Crews, C. M. (2001). Med. Res. Rev. 21, 245. 5. Garc a-Echeverr a, C. (2002). Mini-Rev. Med. Chem. 2, 247. 6. Boccadoro, M., Morgan, G., and Cavenagh, J. (2005). Cancer Cell Int. 5,18. 7. Paramore, A., and Frantz, S. (2003). Nat. Rev. Drug Discov. 2, 611. 8. Palmer, J. T. (1995). J. Med....

Cyclopropylindole Alkylating Agents

This name, although incorrect from the point of view of chemical nomenclature, is usually employed to design a number of antitumor compounds that contain a cyclopropane ring fused to an indole system. The first member of this class was the natural product CC-1065, an extremely potent cytotoxic agent isolated in trace quantities from the culture of S. zelensis in 1978, whose unique structure was confirmed by single-crystal X-ray diffraction in 1981. In spite of its very high in vitro antitumor...

Dna Intercalation And Its Consequences

Many anticancer drugs in clinical use (e.g. anthracyclines, mitoxantrone, dactinomy-cin) interact with DNA through intercalation, which can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking pattern due to Watson-Crick hydrogen bonding. Since many typical intercalating agents contain three or four fused rings that...

Nitrogen Mustards

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...

Mitotic Kinesin Inhibitors

Despite the diverse array of essential spindle proteins that could be exploited as targets for the discovery of novel cancer therapies, all spindle-targeted drugs in clinical use today that we have mentioned in this chapter act on only one protein, tubulin. Kinesins are motor proteins that function to transport organelles within cells, and one group of them (mitotic kinesins) move chromosomes along micro-tubules during cell division, playing essential roles in assembly and function of the...

H h3c ch3 ch3 ch3

4-Hydroxyphenylretinamide (fenretinide) Bexarotene is selective for RXRs (rexinoid) and has been approved by the FDA for cutaneous T-cell lymphoma.59 In combination with chemotherapeutic agents, such as cisplatin and vinorelbine, bexarotene has demonstrated encouraging results in patients with advanced non-small cell lung cancer, and two Phase III trials are currently under way to fully characterize its role in the treatment of this disease.60

Epoxides

The high reactivity of the epoxide ring toward nucleophilic groups in biomole-cules is the basis of the use of ethylene oxide to sterilize substances that would be damaged by heat, including medical supplies such as bandages, sutures, and surgical implements. It has also become quite common as a substructure in side chains of compounds aimed at alkylating DNA38 or other macromolecular targets.39 Diepoxybutane 5.30 is the simplest epoxide which is able to cross-link DNA. Although this compound...

E

E7389 (ER0865), 5-6, 233 EC-16-mitomycin C conjugate, 379 EC-20, 379 Echinomycin, 207 Ecteinascidin 743 (ET-743, trabectedin), 191-182, 341, 390 Edatrexate, 36 Edotecarin, 224 Eflornithine, 422 EGFR (HER-1), 254-255 inhibitors, 258-264 EKB-569, 263 EKI-785, 263 Electroradiochemotherapy, 127 Eleutherobin, 243 Elinafide, 207 Ellipticine, 201 Elomotecan, 221 Enhanced permeability and retention (EPR) effect, 6, 369 Eniluracil (5-ethynyluracil), 28 Enzastaurin (LY-317615), 284 EO4, 186...

Info

Amino acids like aminobenzoic acid derivatives (e.g. FTI-276). L-739750 and FTI-276 were normally employed as ester prodrugs (L-744832 and FTI-277, respectively) in order to enhance their absorption (Fig. 9.29). Despite the encouraging in vivo data obtained for these peptidomimetics, there were reservations regarding their clinical use because of their potential thiol-related toxicity nevertheless, L-744832 has reached clinical trials.108 A combination of the modifications used for the design...

Fused quinoline compounds

TAS-103 is a dual topoisomerase I and II inhibitor that has marked efficacy against various lung metastatic cancers and a broad antitumor spectrum in human xeno-grafts, and it has reached clinical trials for the treatment of solid tumors.21 DNA Chromophore NH2 PO2 Intercalation Chromophore NH2 PO2 Intercalation

Map Kinases

FIGURE 10.9 Inhibition of the NHE3 Na H exchanger by squalamine. 2.5.2. Thalidomide and its analogs Thalidomide was introduced in the 1950s as a sedative that was prescribed for nausea and insomnia in pregnant women. However, it was found to be the cause of severe birth defects in children whose mothers had taken the drug in their first trimester of pregnancy. In 1965, it was serendipitiously discovered that thalidomide was effective at improving the symptoms of patients with erythema nodo-sum...

Ont093 Oc144093

Laniquidar is a potent orally active MDR inhibitor that is undergoing Phase II clinical trials in metastatic breast cancer in combination with taxols.25 The triazi-neaminopiperidine derivative S-9788, which inhibits P-gp specifically with regard to MRPs, showed cardiac toxicity in Phase I clinical trials, but this drawback can be circumvented if this compound is combined with verapamil or PSC-833.26 Other P-pg inhibitors that are in advanced clinical trials as MDR modulators2,29 are SN-22995,...

Eki785

The last four compounds can be considered as active site-directed irreversible inhibitors, since they contain a 4-anilinoquinazoline structural fragment that can be recognized by the ATP site and also an electrophilic a,p-unsaturated carbonyl moiety, responsible for covalent binding to the enzyme. The conserved cysteine residue Cys-773 within the ATP binding pocket seems to be responsible for the nucleophilic attack to this Michael substrate18 Fig. 9.9 .

Tetrahydroisoquinoline Alkaloids

Antitumor natural products belonging to the tetrahydroisoquinoline family have been under study for the last 30 years, starting with the isolation of napthyridi-nomycin.46 They normally bind to DNA by alkylation of specific nucleotide sequences in the minor groove. Most of these alkaloids contain quinone moieties and act by reductive alkylation mechanisms and also by generation of oxygen radicals via their one-electron reduction to a semiquinone species. The presence of either a nitrile or a...

U80224

The structure of CC-1065 and their analogues fits the DNA minor groove curvature, where they bind specifically to AT-rich sequences, followed by irreversible alkylation of adenine N-3 Fig. 6.18A . The halomethyl compounds are activated by cyclization to a cyclopropane derivative after hydrolysis of any protection on the phenolic hydroxyl Fig. 6.18B . As shown in Fig. 6.18A, cyclopropane ring opening needs to be assisted by the electron-withdrawing effect of the carbonyl group. Prior to...

Nh

FIGURE 9.9 Irreversible EGFR inhibitors. Cetuximab IMC-C225 is a chimeric monoclonal antibody that has been approved for clinical use as a second-line treatment for EGF-expressing colorectal cancer. Despite not having demonstrated an improvement in survival it is being tested in combination therapies. Other antibodies directed to the same receptor that are under clinical evaluation are ABX-EGF, EMD-72000 humanized , RH3, MDX-447, and panitumumab fully human .2 3.2. Inhibitors of other receptors...