Platinum carboplatin

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Carboplatin (96) is significantly less toxic in the clinic than cisplatin. Most particularly, it is much less nephrotoxic. Use of a bidentate ligand also ensures formation of a ds complex. Its synthesis begins with cis-diammine platinum diiodide (94) which is reacted with silver sulfate to give cis-diaquodiam mine platinum sulfate (95). This is reacted with the barium salt of 1,1-cyclo-butanedicarboxylic acid to yield carboplatin [23],... 

The platinum(IV) compound that has shown most promise is carboplatin (paraplatin), which received FDA approval in 1990. Features to note in its structure are the use of hydroxy and carboxylate groups to improve water solubility. As noted above, the ammine ligand has been found to need at least one hydrogen, possibly for hydrogen-bonding to phosphate groups in the DNA (Figure 3.116). 

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

Platinum is used therapeutically as ds-platin, carboplatin and iproplatin against tumors (Konig and Schuster 1994). Determination of Pt in serum must be carried out after enrichment procedures followed by GF-AAS. 

In patients who experienced a complete response to first-line chemotherapy and have had greater than a 6-month platinum-free interval, retreatment with a platinum-containing regimen is appropriate. Current National Comprehensive Cancer Network (NCCN) guidelines recommend the combination of carboplatin... 

The main uses for platinum are as a catalyst in the catalytic converter and in fuel cells. And of course platinum, a very expensive metal, is used in jewellery. However, certain platinum-containing compounds are chemotherapeutic agents, examples being cisplatin, carboplatin and oxaliplatin. This explains the synthetic interest in platinum compounds. 

O Dwyer, P. J. Stevenson, J. P. Johnson, S. W. Clinical Status of Cisplatin, Carboplatin, and Other Platinum-based Antitumor Drugs. In Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug Lippert, B., Ed. Wiley-VCH New York 1999, pp 31-72. 

The second criteria, a different activity spectrum, is met by oxaliplatin (Figure 1.9A), the l isomer of [oxalatol f ra/rv-1,2-diaminocyclohexane)platinum (II)], oxaliplatin, [Pt(II)(oxalato)(DACH)]. This platinum agent is used for secondary treatment of metastatic colorectal cancer.77 Oxaliplatin, like carboplatin, has a kinetically slower leaving group, and is also less nephrotoxic than cisDDP. The limiting toxicity of oxaliplatin is peripheral sensory neuropathy, also seen with cisDDP. The neuropathy affects the extremities and increases in incidence and... 

The proposed mechanism starts with a methyl group abstraction on platinum complex 416 with the borane reagent in the presence of diyne 414 (Scheme 105). The square-planar cationic diyne-platinum(n) complex 417 is converted to the octahedral platinum(rv) hydride intermediate 418 through oxidative addition of the hydrosilane. This complex decomposes rapidly with methane release to form another tetracoordinated platinum(n) species 419, followed by platinasilylation of the triple bond. The resulting vinylplatinum 420 undergoes an intramolecular carboplatination to... 

In 1965 Rosenberg et al. (8, 9) accidentally discovered the antiproliferative effect of cis-diammine platinum complexes, which led to the first clinical trials of cis-[PtCl2(NH3)2] 1 in 1971 and resulted in the clinical use of cisplatin worldwide. Cisplatin and carboplatin 2 are the most widely used anticancer drugs, and two other analogs, nedaplatin 3 and oxaliplatin 4 (chiral centers indicated), have recently been approved for clinical use in Japan and France, respectively. 

Chemotherapeutic agents that have significant cancer response when combined with hyperthermia (up to 43°C) include doxorubicin, melphalan, mitomycin C (MMC), mitoxantrone, gemcitabine, etoposide, and especially the platinum-based agents carboplatin and oxaliplatin (Mohamed et al., 2003 Sugarbaker et al., 2005). Agents that do not work well with hyperthermia include irinotecan, paclitaxel, docetaxel, 5-fluorouracil, and floxuridine (Mohamed et al., 2003 Sugarbaker et al., 2005). 

Cisplatin was the first example of a platinum-based chemotherapeutic but it has been followed by others carboplatin, oxoplatin, and cycloplatam. All are variations on the original theme and all find use in the chemotherapy of cancer. 

Capecitabine is an antimetabolite neoplastic and cyclophosphamide is an alkylating neoplastic, both of which can be administered orally. Carboplatin is a platinum compound (antineoplastic). All currently available platinum compounds are administered parenterally via the intravenous route. 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

Carboplatin Carboplatin, cw-diamino-(l,l-cyclobutandicarboxylate)platinum(II), is made from cisplatin by reacting it with a solution of silver nitrate, and then with cyclobu-tan-l,l-dicarboxylic acid to form the desired carboplatin (30.2.5.2) [78,79]. 

Of the wide array of platinum derivatives, carboplatin is the only compound except cisplatin that is used in medical practice, and it differs from cisplatin in the replacement of two chlorine atoms with a cyclobutan-l,l-dicarboxylic acid fragment. Like cisplatin, carboplatin also reacts with DNA to form both internal and external cross-bonds. The range and indications of use are practically analogous to cisplatin. Synonyms of this drug are paraplatin and others. 

Although cisplatin rose to a compound of major interest through its performance in laboratory studies, carboplatin emerged as promising as a second-generation platinum complex on the basis of promising early clinical trial data (65-68). Carboplatin was... 

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