Anticancer drugs 2-

Forgfics and Cserh iti [513] studied 21 anticancer drugs with the intention of determining the relative hydrophobicities of these drugs. Retention of these compounds (e.g., vinblastine, paraplatin, doxorubicin, mitomycin C, methotrexate. 

The leukemia treatment drug 6-meicaptopurine and seven metabolites (e.g., 6-methylmercaptopurine, 6-mercaptopurine riboside, 6-thioguanosine, 6-thioxanthine) were extracted from plasma and separated on a C g column (2 = 295 nm and 330nm). A 50-min 90/10 (hold lOmin) 0/100 (at 50min) 98/2 water [30mM ammonium phosphate pH 3]/methanol)/(60/40 water [30 mM ammonium phosphate pH 3]/methanol) gradient was used [517]. Detection limits were reported as 20-50 nM (analyte dependent). 

8-Chloroadenosine and two serum metabolites (8-chloroinosine and 8-chloro-adenine) were isolated and analyzed on a C g column (2 = 263nm) using an 86/11/3/0.1 water (1% acetic acid)/methanol/acetonitrile/tetrabulylammonium bromide mobile phase [519]. The 8-chloroadenosine peak was severely tailed and eluted last at 21 min. A more effective mobile phase modifier should be investigated (e.g., a TFA/triethylamine mixture). A linear range of 0.1-10 pg/mL and detection and quantitation limits of 0.5 pg/mL (S/N = 2) and 4ng/mL (S/N = 10), respectively, were reported. 

Tamoxifen and two major metabolites (4-hydroxy- and desmethyltamoxifen) were extracted horn breast tumor tissues and separated in lOmin on a C s colunm (A = 265 nm) using an 89/11 methanol/water (1% triethylamine) mobile phase [521], The chosen internal standard was incompletely resolved from the tamoxifen. A linear curve was generated from 2 to 2000 ng injected with a detection limit of 40 pg injected claimed. 

Auraptene, an anticancer phytochemical candidate, was extracted from a wide range of citrus fruits and analyzed on a 40°C Cjg column (A = 325 nm). A 75/25 methanol/water mobile phase generated elution in 6 min. A detection limit of 0.1 ig/g was claimed [522]. 

The chemotherapeutic agent does not differentiate between cancerous and normal cells, and hence causes severe toxicity. Toxic effects are leukopenia, thrombocytopenia, ulceration, diarrhea, azoospermia, infertility, premature menopause, alopecia, and vomiting. On prolonged use, these agents may cause gonadal damage and teratogenicity. 

Anticancer drugs cause bone marrow depression, which is a major side effect and warrants regular monitoring of hematological parameters. Care must be taken when administering anticancer drugs by intravenous injection, and contact should be avoided with skin and eyes. Inhalation of these compounds is dangerous.51 

Drugs used in cancer chemotherapy are cytotoxic drugs, hormones, plant derivatives, radioactive isotopes, and miscellaneous agents (e.g., procarbazine, hydroxyurea, mitotane). The plant-based drugs vincristine, vinblastine, vinorel-bine, etoposide, and campothecins. Radioactive isotopes, such as 131 iodine (131 I), are used in the treatment of thyroid tumors. Cytotoxic drugs (e.g., cis-platin, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate are used for the treatment of cancer. 

Blood pressure control Diabetes - insulin mimics Antimicrobials 

Metal-containing coordination compounds that show a capacity to cure or control a disease have grown remarkably in number and range of applications in recent decades. Their form covers a wide range of metal ions, ligands and stereochemistries. Some examples appear in Table 9.1. It is not the role of an introductory text to cover applications in depth, but it is appropriate to illustrate their applications and show how they link with our basic concepts of coordination chemistry. 

Cisplatin acts by binding to DNA and inhibiting replication in the cancer cell. Substitution reactions of coordinated chloride ligands are the key chemistry in reactions of cisplatin in a human cell. Most cisplatin circulates in the blood unchanged over a short timeframe, as 

The drug cisplatin, its reaction pathways in the cell and an example of coordination to DNA, leading to distortion of the double helix (cisplatin-DNA binding figure reproduced from the Protein Data Bank DOI 10.2210/pdblaio/pdb). 

Various modes of coordination of the platinum(II) drug cisplatin to bases in DNA strands, following initial chloride hydrolysis a guanine N-donor (G) is favoured. Actual models determined from structural studies of intra- (at left) and inter-strand (at right) coordination to DNA oligomers (drawn from the Protein Data Bank DOI 10.2210/pdblddp/pdb and 10.2210/pdblksb/pdb) are also shown. 

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Folic acid, 4-amino-4-deoxy-10-methyl-, 1, 164 3, 325 as anticancer drug, 1, 263 biological activity, 3, 325 Folic acid, 4-amino-10-methyl-toxicity, 1, 141 Folic acid, 7,8-dihydro-biosynthesis, 3, 320 synthesis, 1, 161, 3, 307 Folic acid, 4-dimethylamino-hydrolysis, 3, 294 Folic acid, 5-formiminotetrahydro-biological activity, 3, 325 Folic acid, 5-formyl-5,6,7,8-tetrahydro-biological activity, 3, 325 chirality, 3, 281 occurrence, 3, 325 Folic acid, 10-forfnyltetrahydro-biological activity, 3, 325 Folic acid, 5,10-methenyl-5,6,7,8-tetrahydro-biological activity, 3, 325 chirality, 3, 281 Folic acid, 5-methyl-chirality, 3, 281 Folic acid, 9-methyl-toxicity, 1, 141... 

In spite of the fact that few cycloalkynes occur naturally, they gained recent attention when it was discovered that some of them hold promise as anticancer drugs. (See the boxed essay Natural and Designed Enediyne Antibiotics following this section.)... 

Enediynes hold substantial promise as anticancer drugs because of their potency and selectivity. Not only do they inhibit cell growth, they have a greater tendency to kill cancer cells than they do normal cells. The mechanism by which enediynes act involves novel chemistry unique to the C C—C=C—C C unit, which leads to a species that cleaves DNA and halts tumor growth. 

Heterocyclic analogs of A-nitrosoureas as anticancer drugs 97CRV829. 

The cis isomer ( cisplatin ) is an effective anticancer drug. This reflects the ability of the two Cl atoms to interact with the nitrogen atoms of DNA, a molecule responsible for cell reproduction. The trans isomer is ineffective in chemotherapy, presumably because the Q atoms are too far apart to react with a DNA molecule. 

The unusual tolyporphin was isolated from the Pacific cyanophyte Tolypothrix nodosa and it has been shown that tolyporphin eliminates the multidrug resistance (MDR) in certain carcinoma sublines thus potentiating the cytotoxicity of anticancer drugs in these cell lines.2... 

The mitomycins do not react directly with DNA, but require prior activation by reduction of the quinone. This property of bioreductive activation has inspired the design and development of synthetic anticancer drugs that are also activated by reduction, as this is expected to confer a degree of tumor selectivity [45, 46]. Many solid tumors are short of oxygen relative to normal tissue, so reductive activation of the mitomycins and other bioreductive drugs can proceed in tumors, while it is inhibited by the oxidizing environments in normal tissues. 

Yart A, Mayeux P, Raynal P (2003) Gabl, SHP-2 and Other Novel Regulators of Ras Targets for Anticancer Drug Discovery. Curr Cancer Drug Targets 3 177-192... 

A number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The first drug in this area is imatinib mesylate, which targets... 

Miltefosin The antileishmanial activity of this anticancer drug was discovered in the mid-1980s. It is the first oral drug available to treat visceral and cutaneous/mucocutaeous leishmaniasis. However, the registration process is slow. 

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

Also nonkinase molecules might be important targets for anticancer drugs. For instance, the activity of the mitotic kinesin Eg5 (KSP, kinesin-5) can be inhibited by small molecules (e.g., monastrol, KSP-IA) resulting in mitotic defects associated with the induction of apoptosis. 

Due to their promising activities in preclinical investigations, the first clinical data for these new generations of anticancer drugs are eagerly awaited. 

Bryostatins are another class of compounds that bind to the Cl domain and result in acute activation of PKC. However, unlike phorbol esters, these marine natural products have antitumor effects. Bryostatins are currently in phase II clinical trials and show promise as anticancer drugs, particularly when combined with other adjuvant therapy. 

Anticancer drugs originally extracted from the cortex of Taxus brevifolia or Taxus baccata. They block cell division by inhibiting tubulin depolymerization. Two... 

Thiopurine S-methyltransferase is an enzyme which inactivates the anticancer drug 6-mercaptopurine by S-methylation. 

TNF was originally identified because of its cytotoxic activity against some tumor cell lines and its ability to induce hemorrhagic necrosis of solid tumors in various animal models. However, the clinical use of TNF as an anticancer drug has been so far limited by its severe cardiovascular side effects. Therefore, TNF treatment is limited to regional and local administration of high doses of TNF, often in combination with chemotherapy, as accomplished in isolated limb and isolated hepatic perfusion (ILP and IHP, respectively) [5]. In the case of ILP, typically metastases are treated, patients benefit from this procedure by salvage of limbs from a loss by amputation. 

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