Camptothecin water-soluble derivatives

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. 

Camptothecin is a plant alkaloid obtained from the Camptotheca acuminata tree. It was first evaluated clinically, as a sodium salt, in the 1960s and 1970s, but was abandoned because of severe and unpredictable hemorrhagic cystitis (3,4). Irinotecan (CPT-11) and Rubetecan are semisynthetic, water-soluble derivatives of camptothecin possessing... 

Kunimoto T, Nitta K, Tanaka T, et al. Antitumor activity of 7-ethyl-10-[4-(l-piperidino)-l-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, againstmurine tumors. Cancer Res 1987 47(22) 5944-5947. 

Another important anticancer natural product is camptothecin, an alkaloid derived from the Chinese tree Camptotheca acuminata Descne. A semisynthetic water-soluble derivative of camptothecin known as ironotecan (Topotecin , Campto ) was introduced in Japan in 1994 for the treatment of lung, ovarian, and cervical cancers. Unlike Taxol, camptothecin acts by inhibition of the enzyme topoisomerase I. 

Sawada, S., Yaegashi, T., Furuta, T., Yokokura, T., Miyasaka, T. Chemical modification of an antitumor alkaloid, 20(S)-camptothecin E-lactone ring modified water-soluble derivatives of 7-ethylcamp-tothecin. Chem. Pharm. Bull. 1993, 41, 310-313. 

A number of synthetic strategies for the preparation of camptothecin were developed in the 1970 s and early 1980 s [49-55], and these efforts culminated in several successful total syntheses, the first by Stork and Schultz [56], Discontinuation of the early clinical studies of camptothecin dramatically reduced the research effort devoted to investigating new methodologies for the total synthesis of this alkaloid. In the late 1980 s, however, the discovery of the unique biological mode of action of camptothecin, and the development of water-soluble derivatives such as CPT-11 [21] and topotecan [23], revived interest in the development of practical methods for the synthesis of camptothecin. 

In an effort to improve the water solubility of camptothecin, Rahier et al. [50] synthesized four 20-O-phosphate derivatives (VI). These compounds are freely water-soluble, stable to physiological pH, and stabilize the human topo I-DNA covalent binary complex with the same sequence-selectivity as camptothecin itself All four compounds inhibited the growth... 

Water soluble 7-substituted quaternary anunonium salt derivatives of 10,11 -(methylenedioxy) - and 10,11 -(ethylenedioxy)-(20S)-camptothecin 216 (Figure 9) are synthesized via the Friedlander reaction followed by nucleophilic displacement with an aromatic amine. All are more potent than camptothecin in the in vitro cleavable complex assay (96JME713). 

Simple tertiary amines can be grafted to a carbon skeleton, either by exchange reactions or by Mannich reactions. The hydrochloride salt of the camptothecin derivative (a) (Figure 38.15) is soluble in water at concentrations up to 1 mg/mL the comparable value for camptothecin itself is 0.0025 mg/mL. Similar results were obtained in solubilizing the benzodiazepine (b) and the quinazolinone (c). The adenosine Ai antagonist KW-3902 (d) was solubilized in an original manner by converting it to an amidinic and cyclized bioisostere (e). ... 

Simple tertiary amines can be grafted to a carbon skeleton, either by exchange reactions or by Mannich reactions. The hydrochloride salt of the camptothecin derivative (Fig. 36.14) in (a) is soluble in water at concentrations up... 

---