Camptothecin topotecan

HCPT (0.364 g 0.01 mmol) and 40% aqueous dimethylamine (12 ml) was added in dichloromethane (50 ml) in which anhydrous potassium carbonate (2.17 g, 15 mmol) has been suspended. The reaction mixture was stirred at room temperature for 5 h, then filtered and solid extracted with ethylacetate (20 ml). The solvent is evaporated in vacuo giving a residue. The residue was triturated with 0.5% aq HCI (50 ml) to dissolve the water-soluble adduct. Water-soluble were partitioned with petroleum ether (3 times 50 ml) and followed by ethylacetate (3 times 50 ml). The aqueous layer was lyophilized as an off white hydrochloride salt of 9-[(dimethylamino)methyl]10-hydroxy(20S)-camptothecin (topotecan hydrochloride) yield 0.236 g (65%). 

Topotecan (toe poe TEA can) has recently been approved for the treatment of metastic ovarian cancer. It is a semi-synthetic derivative of an earlier drug, camptothecin. Topotecan has a complicated multiring structure containing a lactone ring that is essential for activity. The drug inhibits topoisomerase I, which is essential in the replication of DNA in human cells (Figure 38.23). Unlike etoposide, which inhibits... 

Although not listed in the tables, at least four other natural product drugs have given yeoman service in the antitumor area. The first of these is paclitaxel (Taxol ) which sold US 1.6 billion in 2000 this is followed by the vinca alkaloids vinblastine and vincristine. Completing the quartet are the natural product-derived epi-podophyllotoxin derivatives teniposide and etoposide and the materials derived from camptothecin, topotecan and CPT-11. These will probably not be the only natural product drugs in the antitumor field, as can be seen by inspection of Table 6.3, where Cragg and Newman recently reported on the source... 

Camptothecins (irinotecan, topotecan) are derived from the bark of the Chinese tree Xi Shu (Camptotheca accuminata). They inhibit topoisomerase I thus effecting double strand breaks. Unwanted effects include diarrhea and reversible bone marrow depression. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

In a similar way (and as described for the aromatic isocyanides), aliphatic a, 3-un-saturated isocyanides can also be used, leading to similar structures with a cyclo-hexano instead of a benzo moiety [84]. Based on the approach using aromatic isocyanides, a small library of about 20 camptothecin derivatives has been prepared, of which irinotecan and topotecan have entered the clinical treatment of cancer [85]. For the synthesis of the camptothecin derivatives, 3-206 was alkylated with the appropriate propargylic bromides 3-207 to give 3-208, which were irradiated in benzene at 70 °C, together with the respective isocyanide 3-209 and hexamethylditin... 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Topotecan -semisynthetic camptothecin topoisomerase 1 inhibitor -bone marrow suppression -nausea and vomiting -mucocutaneous effects (mucositis, stomatitis) -constitutional symptoms—fatigue, anorexia, malaise -hematuria -renal insufficiency -hypertension -hepatotoxicity... 

First generation of topi inhibitors were developed as drugs from camptothecins, a family of compounds derived from wood and bark of the Chinese tree Camptotheca acuminata) [9, 10], Many of these are already in clinical use or clinical trials, including irinotecan, topotecan, exatecan, rubitecan, and lurtotecan. Irinotecan (CPT-11) is bioactivated in liver by carboxylesterase to the active metabolite SN-38, 1000-fold more active [11]. Irinotecan received in 1998 FDA approval for treatment of metastatic colorectal cancer after failure of treatment with 5FU [12],... 

Topotecan is the second camptothecin derivative it is itself an active drug, and received FDA approval as second line therapy in metastatic ovarian cancer (1996) and in SCLC (1998) [13], In addition, representatives of a second generation of topi inhibitors, the homocamptothecins, are now being developed for chemotherapy, e.g., BN-80915 and BN-809271 [14]. 

Representatives of another important class of plant-derived semisynthetic compounds are the camptothecin (27) derivatives, irinotecan (28) and topotecan (29). Camptothecin (27) was originally discovered as an antileukemic agent in a mouse model when isolated from Camptotheca acuminata Decne. Compounds (28) and (29) are both employed in cancer chemotherapy. These substances are important mechanistically because of their activity against the enzyme, topoisomerase I. These compounds were designed to address efficacy and toxicity concerns with the parent compound, camptothecin, and its sodium salt. ... 

Camptothecins as Antitumor Agents Clinical Pharmacology of the CPTs Interaction with Irradiation Topotecan Irinotecan... 

The topoisomerase I inhibitors include irinotecan and topotecan. They are water-soluble camptothecin analogues. Both are administered by intravenous infusion. Their cytotoxicity effects are exerted through interaction with the topoisomerase I-DNA complex, eventually leading to cell death. 

Camptothecin Topoisomerase Inhibitors. The camptothecins (e.g., topotecan, 7.84, irinotecan, 7.85) are natural products that function as topoisomerase I enzyme inhibitors. 

The camptothecins are natural products that are derived from the Camptotheca acuminata tree, and they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of the enzyme results in DNA damage. Topotecan is indicated in the treatment of patients with advanced ovarian cancer who have failed platinum-based chemotherapy and is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and for this reason caution must be exercised in patients with abnormal renal function, with dosage reduction being required. 

Many anticancer agents have their origins in pharmacognosy, including paclitaxel, etoposide, and the camptothecin analogues, topotecan and irinotecan, to name just a few. The dolastatins are a unique class of compounds isolated from the Indian Ocean sea-hare Dolabdla auricularia that are referred to as depsipeptides,... 

Induction of strand breakage may result from inhibition of topoisomerase. The epi-podophyllotoxins etoposide and tenoposide interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p.276) these agents cause strand breakage by inhibiting resealing. The te-cans topotecan and irinotecan are derivatives of camptothecin from the fruits of a Chinese tree (Camptotheca acuminata). They inhibit topoisomerase I, which induces breaks in single-strand DNA. 

Cositecan (Karenitecin , BNP 1350) 54 (BioNumerik and ASKA Pharmaceutical) is currently being evaluated in a Phase III trial for the treatment of patients with advanced ovarian cancer who have become resistant to platinum and taxane drugs.110 Cositecan 54,111 114 which is also being evaluated against solid tumours in a Phase I trial, is an orally bioavailable, lipophilic 7-[2-(tri-methylsilyl)ethyl] derivative of camptothecin 55 which is less sensitive to both common and camptothecin-specific resistance mechanisms. Camptothecin 55 was first isolated in 1958 from Camptotheca acuminata (Nyssaceae) and its structure was reported in 1966.115 117 Camptothecin 55 was later shown to be a topoisomerase I inhibitor two camptothecin derivatives, topotecan and iri-notecan, are approved for chemotherapy use. 

In addition to the remote or active loading techniques mentioned above, metal complexation reactions have been demonstrated to achieve accumulation of doxorubicin in liposomes [148,149], Furthermore, copper-topotecan complexation has been recently seen to mediate drug accumulation into liposomes and is proposed as a methodology to prepare liposomal camptothecin formulations [72],... 

Today, several soluble camptothecin derivatives such as topotecan (3), 9-aminocamptothe-cin (4) and irinotecan (CPT-11) (5) are of clinical importance. Positive results were achieved, especially against intestinal, breast and ovarian can-... 

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