Boronated Polyamines

Polyamines, such as spermidine, spermine, and putrescine, are essential for the growth and proliferation of all the cells (Figure 2.24).52 The presence of quickly dividing cells, such as cancer cells, is closely correlated with an HH H H H u i i i i ,H H-N-C-C-C-C-N-H H I I I I H H H H H H H N C C C-C-N C C- C N- H hi, i i i i i i i i h HH H H H H H H H H H Figure 2.24 Naturally occurring polyamines increase in the cellular polyamines.53 Because of their tumor specificity, the polyamines have...

References

Seddon, The chemistry of ruthenium, in Topics in Inorganic and General Chemistry, Monograph 19, Amsterdam Elsevier, 1984. 2. G.W. Osann, Philosophical Magazine, 2, 391-392 (1827). 3. K.K. Klaus, Philosophical Magazine, 27, 230-231 (1845). 4. D.R. Lide, Handbook of Chemistry and Physics, 77th edition, London CRC Press, 1996-1997. 5. M.J. Clarke, Ruthenium complexes, in Metal Complexes in Cancer Chemotherapy, Weinheim B.K. Keppler (ed.), New York VCH, 1993. 6. M.J. Clarke,...

The Biochemistry of Titanium

Despite being one of the most abundant metals, titanium, together with aluminum, is apparently not used by organisms. Both elements do not satisfy the rigorous requirements for essentiality in studies to date. Titanium inhibits numerous hydrolytic enzymes, and as titanate can be stimulatory, but there is no evidence that it is bioessential.5 At least two explanations can be suggested to account for these findings.2 One suggestion is that despite its abundance, titanium may not be sufficiently...

Antitumour Potential of Triorganotin Carboxylates

Triorganotin compounds, which probably adopt four-coordinate distorted tetrahedral structures in non-coordinating solvents as deduced from NMR studies, are quite well known as bactericides and fungicides59,60 (Figure 22.3). Figure 22.3 Likely chemical structure of a triorganotin carboxylate (type 3) in solution Table 22.3 Typical ID50 values (ng ml) of triorganotin carboxylates tri-n-butyl- and triphenyl-terebates (see Table 22.2 for the structure of terebate) Table 22.3 Typical ID50 values (ng...

Cobalamin conjugates as drug delivery devices

Most of the front-line chemotherapeutic drugs such as doxorubicin, taxol, etopo-side and the alkylating agents have a dose-limiting toxicity that arises from interaction of the drug with an organ system that is remote from the site of cancer. If these cytotoxic drugs could be delivered selectively to cancer cells, their therapeutic index would be greatly increased and the serious side-effects such as bone marrow suppression, cardiotoxicity, nephrotoxicity, hepatotoxicity, neuro-toxicity, hair...

Other medicinal applications

Anti-cancer activities of antimony agents have also been reported. Antimony tartrate has been found to be cytotoxic in vitro to various lung cancer cell lines with IC50 ranging from 4.2 to 322 mgml1. The complex was found to be as effective as those clinically used anti-cancer drugs such as cisplatin and doxo-rubicin.30 Other antimony compounds (including organometallic complexes) have been tested in both cell cultures and animal models, and have displayed moderate activities.31 The anti-cancer...

[ReVoxoDMSA

The Re(V)-oxo complex of meso-2,3-dimercaptosuccinic acid (DMSA) has been investigated as a therapeutic analogue of technetium radiopharmaceutical, which is known as 'pentavalent technetium-99m-DMSA' and which is used as an imaging agent in medullary thyroid carcinoma. The rhenium complex is a mixture of three isomers each with square pyramidal Re(V) (Figure 24.23).4 The biological properties of 188Re(O)DMSA have been investigated in humans with medullary thyroid carcinoma. The investigation...

Toxicity of Rhodium Complexes

There are no data on rhodium involvement in either human or animal biochemical systems. Studies of the 105RhCl3 metabolism in rats administered via the oral, intravenous and intramuscular routes revealed that rhodium was poorly absorbed. Initial rapid elimination occurred in the urine and later via the gastrointestinal tract. Rhodium was mainly accumulated in kidney and liver, but minor fractions were found in many soft tissues. The biological half-life of 105Rh varied between 4.3 and 16.5...

Peptic ulcer disease

Peptic ulcers are thought to arise as a result of excessive amounts of gastric acid and pepsin or negligible mucosal resistance.14 It is logical, then, that any medication to combat the problem relates to the aforementioned factors and enhances the corresponding defense mechanism(s). Among the various categories of anti-ulcer drugs in the market, specific families contain aluminum. These include (a) anti-secretory medication and antacids and (b) mucosal protection agents. A significant...

Specific Organosilicon Compounds

There are several classes of organosilicon compounds lacking organic analogues and groups of compounds with specific properties based on the distinguished characteristics of silicon. Silicon can form stable penta-8,12 and hexa-coordinated129,135 organic derivatives which is possible for carbon only in some special cases. One of such class of compounds with penta-coordinated silicon is silatranes (22) having a wide variety of biological effects.6 9,12,13 Silatranes bearing aryl7,8 and...

Zinc and prostate cancer

Etiologic factors that initiate and enhance the progression of prostate malignancy are beginning to emerge. One major research focus is the role of diet and nutrition. Dietary factors possibly linked to prostate cancer are numerous however, the most provocative data focus attention upon those nutrients and phytochemicals involved in oxidative defense. A clear understanding of how anti-oxidants may protect the prostate from the genetic damage that is associated with tumor development remains...

The history of lithium therapeutics

Garrod described the medical use of lithium in 1859 for the treatment of rheumatic conditions and gout - and in particular 'brain gout'. The hypothesis behind the use of lithium at this point was based on its ability to dissolve nitrogen-containing compounds, called urates or uric acid, which were thought to build up in the body giving rise to many illnesses. This is certainly true for gout, but the idea was extended to include many other human physical disorders. By the 1880s, Carl Lange and...

Alginate Raft Formulations

Heartburn is one of the commonly experienced gastrointestinal symptoms. In fact it is the primary symptom of gastro-oesophageal reflux disease (GERD).45 The symptoms emerge, most often, following oesophageal influx of gastric acid. Thus, heartburn is strongly correlated with acidification of the oesophagus. The heartburn symptoms usually emerge in individuals after meals or nocturnally, often followed by burning substernal pain. The phenomena of gastrointestinal reflux and regurgitation are...

Examples where introduction of ferrocene has resulted in a loss or no change in activity

The replacement of the aromatic ring in some non-steroidal anti-inflammatory agents (fenclofenac, flurbiprofen, fenbufen, tolmetin) by ferrocene did not improve anti-arthritic or platelet aggregatory activities in the resulting com-pounds.19 It was concluded that ferrocene is not an appropriate bioisostere for the phenyl or pyrrole ring. Ferrocene-containing penicillins and cephalosporins20 and ferrocene-containing rifamycins21 have been evaluated and found to be no better than the original...

Cancer prevention

Studies as early as 1969 suggested that there was an inverse correlation between dietary selenium levels and cancer mortality rates.45 Accompanying the discovery of the enzyme GPx, the chemopreventative action of selenium was initially attributed to its presence in anti-oxidant enzymes such as GPx and other selenoproteins. In 1996 Clark found that selenium supplementation, 200 mg day in the form of selenium-enriched yeast, reduced the risk of prostate, colon and lung cancer by up to 48 in...

Antioxidants and antiinflammatory agents

Reactive oxygen species (ROS) are involved in many biological processes including the inflammatory response. ' ' Ebselen (1) is an anti-oxidant and anti-inflammatory that has undergone Phase III clinical trials as a neuroprotective agent and is soon to become the first synthetic organoselenium therapeutic released on the market. Selenium is not liberated from Ebselen 1, and as such it is relatively non-toxic. The anti-inflammatory action of Ebselen 1 is attributed to its ability to interfere...

Mechanism of Action of Cisplatin

Cisplatin Action

Broadening the chemotherapeutic arsenal depends on understanding existing agents with a view toward developing new modes of attack. In the 35 years since the discovery of the anti-tumor activity of cisplatin, laboratory studies have provided considerable information as to how the drug exerts its antitumor effects and how some tumors are, or become, resistant to this drug. Although a number of features of the mechanism underlying the anti-tumor effects of cisplatin have been thoroughly...

Bipolar disorder and schizophrenia

As described above, lithium inhibits GSK-3 and inositol phosphate signalling and both pathways have therefore been suggested to be involved in BD. The best current hypothesis describing how lithium functions in the treatment of BD is the 'inositol depletion' hypothesis of Berridge et al.40 This theory suggests that the cause of BD may be overactive InsP signalling in the brain of these patients, and this may be reduced by the inhibitory effect of lithium on InsP signalling (Figure 1.4). In...

Copper Thiosemicarbazone Complexes

The anti-tumour potential of quinonoidal compounds is known since 1974 and several 1,2-napthaquinone derivatives behave as anti-cancer compounds.26 28 Recently, the synthesis and structural characterization of metal conjugates of 1,2-naphthaquinone (NQTS, Scheme 12.2) along with their anti-tumour activities against the MCF7 breast cancer cell line have been studied.29 Thiosemi-carbazonates have been intensively studied due to their inhibitory action on the DNA enzyme ribonucleotide diphosphate...

Gestational hypertension preeclampsia and eclampsia

Gestational hypertension is the most frequent cause of hypertension during pregnancy and the rate varies between 6 and 17 .14,15 Some women with gestational hypertension will subsequently progress to preeclampsia and the rate of progression depends on gestational age at the time of diagnosis. The rate reaches 50 when gestational hypertension develops before 30 weeks gestation. Preeclampsia is primarily defined as gestational hypertension plus proteinuria. Preeclampsia is considered severe if...

Boron Compounds as Therapeutic

Geeta Rana, Kamesh Vyakaranam, John A. Maguire and Narayan S. Hosmane 2.1 Boron Neutron Capture Therapy 19 2.2 Classes of Boron Compounds for Potential Use 2.2.2 Boron-containing amino acids and related peptides 24 2.2.3 Boron-containing nucleic acid precursors 27 2.3 Phosphates, Phosphonates and Phosphoramidates 31 2.5 Boron Analogues of Pyrophosphates 33 2.6 Boronated Polyamines 34 2.9 Lipids and Phospholipids 37 2.10 Radiation Sensitizers 38 2.11 Cyclic Thiourea Derivatives 38 2.12 Central...

Antihypertensives

May and co-workers have developed a series of phenylaminoethylselenides (PAESe) 19 that have anti-hypertensive properties.105 107 PAESe's antihypertensive activities appear to result from inhibition of dopamine -mono-oxygenase (DBM).105 DBM catalyzes the conversion of dopamine to noradrenalin and is dependent on ascorbate for catalytic activity (Figure 17.6). PAESes inhibit DBM by depleting ascorbate in the vesicles of chromaffin cells. DBM oxidizes PAESe 19 to the selenium oxide 20 using...

Titanocene Dichloride

7.5.1 Chemistry and anti-cancer activity In 1979, Kopf and Kopf-Maier reported42 on the first metallocene with antitumor activity, the complex Cp2TiIVCl2 (bis( -cyclopentadienyl)titanium(IV) dichloride, titanocene dichloride). The red crystalline titanium(IV) complex was first prepared by Wilkinson and Birmingham in 1954.43 The two planar C5H5 cyclopentadienyl rings each have a delocalized negative charge and are coordinated to the metal center via pentahapto metal carbon coordination in a...

Antitumor Activity of Carboplatin Oxaliplatin and Nedaplatin

The leaving group of carboplatin is a less labile cyclobutanedicarboxylato ligand which undergoes a slower rate of aquation than the chlorides in cisplatin. Unfortunately, carboplatin exhibits cross-resistance with cisplatin so that although less toxic and more easily administered than cisplatin, it has not demonstrated any substantial advantages over cisplatin.4,5 The therapeutic index defined by the efficacy versus toxicity profile even favors cisplatin in most tumor systems (in testis,...

Toxic Side Effects of As2O3

In the treatment of APL patients, the side effects of As2O3 appear to be mild. In contrast to many other chemotherapeutic agents, it causes no myelosuppression. Instead, As2O3 induces leukocytosis in about 50 of patients.11,13,36 The leuko-cytosis can resolve in all cases without chemotherapy.87 The APL patients on As2O3 can also develop retinoic acid syndrome (RAS)-like symptoms such as fever, skin rash and edema, which can be readily relieved by steroid administra-tion.88 Other mild effects...

Budotitane

7.4.1 Chemistry and anti-cancer activity The TiIV(bzac)2(OEt)2 complex (budotitane, bzac 1-phenylbutane-1,3-dionate benzoylacetonate) was the first non-platinum complex tested in clinical trials.18 Budotitane and related bis( -diketonato) metal complexes can be synthesized from the corresponding metal tetrahalogenides and the diketonates in an anhydrous organic solvent. Budotitane was selected from about 300 related derivatives for further development. The structure activity relation of...

Titanium Anticancer Drugs

After the discovery of the tumor-inhibiting properties of cis-diammine dichloro-platinum(II) (cisplatin) in 196912 and its routine use as a leading cytostatic drug since 1979,13 there has been increasing interest in the development of new anti-tumor metal agents including non-platinum metal complexes. Among these, two monomeric titanium(IV) complexes have qualified for clinical trials (Figure 7.1) TiIV(bzac)2(OEt)2 (budotitane) and Cp2TiIVCl2 (titanocene dichloride). Relevant reviews on...

Nitrogen and other donor atoms

The cyclopalladate complexes of imidazoline (Imd) derivatives PdCl2 (C6H5CH2C3H5N2)2 and PdCl(SEt2)(C6H4-C3H5-N2)2 exhibited important cytotoxic activity against HL-60, with IC50 values, lower than 10 mg ml, close to those of cis-DDP and considerably higher than the free ligand. Thus, the cytotoxic activity of free Imd increased upon coordination with Pd(II).41 Two diastereomeric cyclopalladated complexes arising from Pd2(mpba)2(m-OAc)2 (mpba is 4-methoxy-benzoylbenzylideneimine, Figure 21.8b)...

Examples where introduction of ferrocene has resulted in enhanced activity or a change in activity profile

The replacement of one of the phenyl rings in tamoxifen by ferrocene has given rise to a group of compounds called ferrocifens.24,25,26 Tamoxifen is a selective estrogen receptor modulator that is used against breast cancer. Its activity is limited to 'estrogen receptor positive' tumours that constitute about 60 of breast cancer cases. The ferrocifens were synthesized in an attempt to overcome the shortcomings of tamoxifen as an anti-tumour agent. The triphenylethylene-like framework of...

Mechanism of Action of Carboplatin Oxaliplatin and Nedaplatin

Carboplatin forms a similar spectrum of DNA adducts as cisplatin with slightly different sequence preferences.22 Concentrations of carboplatin approximately two orders of magnitude higher are needed to obtain DNA platination levels equivalent to cisplatin. Conformational alterations induced in DNA by carbo-platin in cell-free media have been characterized23 and the changes of non-denaturational character similar to those observed for cisplatin at the same level of DNA platination have been...

Humans

Manganese deficiency in humans is uncommon but it has been reported in several laboratory-induced experiments.16 The first was by Doisey who inadvertently fed a low-manganese diet (0.34mg day) for 3.5 months to a subject on a semi-purified vitamin K-deficient diet. Symptoms that were not ameliorated by restoration of vitamin K were reddening of a black beard and hair, diminished hair and nail growth, hypocholesterolemia and a scaly, transitory dermatitis. The last two symptoms were observed...

Applications of antimony drugs as antileishmanial agents

Antimony-based drugs have remained the major therapeutic treatment in the clinic for decades.19 The use of antimony chemotherapy increases the survival rate of those patients with Leishmania infection to over 90 .20 Although its main action is concentrated only on the visceral leishmaniasis, other forms of the disease are also responsive. The major disadvantages are a long treatment period, requiring hospitalization, and the need in many cases for subsequent course of treatment for an effective...

RhodiumIII complexes

As rhodium III coordination complexes have a d6 electronic configuration, they are isoelectronic with Ru II and Pt IV complexes which are interesting anti-tumor complexes, e.g. OC-6-43 - PtCl2 OOCMe 2 CyNH2 NH3 Cy cyclohexyl JM216 , an orally active anti-tumor agent. Rhodium III complexes generally have an octahedral structure and are inert complexes nevertheless, many of the Rh III coordination complexes tested show considerable anti-tumor and anti-microbial activity. The meridional complex...

Copper Purine Derivatives Complexes

The synthesis, characterization and biological anti-tumour and anti-proliferative activity of new mononuclear or binuclear copper II complexes with 6- 2-chlorobenzyl-amino purine HL1 A and 6- 3-chlorobenzylamino purine HL2 B Scheme 12.1 have been reported by Travnycek etal.,22 the composition of the complexes depending on the molar ratio of the reactants and the pH of the medium. The mononuclear complex Cu H L2 2Cl3 Cl H2O 1 was isolated and green-blue crystals suitable for single-crystal X-ray...

Antibacterial and Antiparasitic Activity

Many Rh I , Rh II and Rh III complexes are active against malaria, leish-maniasis, trypanosomes, bacteria and algae. The anti-malarial activity of RhCl COD CQ CQ chloroquine is similar to that of chloroquine diphosphate.79,80 However, chloroquine complexes with other metals ruthenium and gold are more active.79 Numerous rhodium complexes were investigated for the treatment of leishmaniasis.79,81 83 Rhodium III cationic complexes containing 2-hydroxybenzothiazole are very efficient...

Cancer

Cancer is a malignant tumor that occurs as a result of abnormal and uncontrolled cellular divisions. Manganese may be critical in the development of some cancers as tumor cells usually have low concentrations of SOD2 and ROS play a role in tumor formation. Also, transfection with SOD2 enhances cellular differentiation and inhibits malignant transformation.12,51 A Mn salen mimetic of superoxide dismutase and catalase EUK-135 has been found to exert pharmacologic efficacy in cell survival...

Targeting Cells with GdIII Chelates

Currently, an important task in the field consists of providing the CAs with targeting capabilities. After the implementation of extracellular and blood pool systems, the new frontier in MRI is represented by the possibility of imaging molecular targets that act as signatures of a given pathology. This will allow early diagnosis of diseases as the detection of an altered biochemical process largely anticipates the anatomical changes that are at the basis of current diagnostic modalities....

Germatranes

The next group of biologically active organogermanium compounds are germatranes 3 - tricyclic organogermanium derivatives of triethanolamine containing a hypervalent germanium atom with a transannular bond to nitrogen bond length 2.01-2.29 A which is responsible for their chemical stability.122 Several methods for the preparation of germatranes have been elaborated. The reaction of tetra-alkoxy- or trialkoxy-germatranes with triethanolamine occurring under mild conditions in the presence of a...