Camptothecins: a SAR/QSAR study.

Camptothecin (CPT, I), a unique pentacyclic quinoline alkaloid originally isolated from a native tree of Tibet and China called Camptotheca acuminata in latin and Xi Shu in Chinese, is one of the prominent lead compounds in anticancer drug development.1-3 It has been identified from the early assessments that the importance of 20S chiral carbon of CPT for their activity and also pointed out a dynamic equilibrium between the close-ring lactone and open-ring carboxylic acid forms at physiological pH. Due to the extremely poor solubility of CPT in water, clinical trials were initiated using its water-soluble sodium salt (II; Figure 1). The results were disappointing: biological activity was weak relative to xenograph models and unexpected side effects including hemorrhagic cystitis and myelotoxicity, which resulted in suspension of the trials.4,5 Later on, it was established that the R-hydroxy lactone ring moiety must be intact for antitumor activity and that this ring was being opened in the preparation of the sodium salt.6 In a conformational analysis, torsional parameters for the MM3(96) force field were obtained by Carrigan et al.7 for the R-hydroxy lactone and CPT using ab initio calculations on representative compounds containing the critical dihedral angles. MM3(96) predicts two distinct “boat-like” conformations for the R-hydroxy lactone moiety. The low-energy lactone conformation predicted by MM3(96) is in good agreement with X-ray crystal structures of CPT iodoacetate and 7-ethyl-10-(4-piperidino)piperidinylcarbonyloxy CPT HCl as well as the ab initio structure of a CPT-like R-hydroxy lactone. Nearly 20 years later, the discovery that the primary cellular target of CPT is DNA topoisomerase I (topo I) was the breakthrough that renewed interest in this agent and led to synthesizing more water-soluble analogues.8-10 Two of them, topotecan (Hycamptin, III) for the clinical treatment of the ovarian and small-cell lung cancers,11-14 and irinotecan (Camptosar or CPT-11, IV)15,16 for the metastatic colorectal cancers have already gained approval by the Food and Drug Administration (FDA) of the U.S.A.17,18 Irinotecan is a prodrug that is converted into their active metabolic form 10-hydroxy-7-ethylcamptothecin (SN-38, V; Figure 2). These two drugs (topotecan and irinotecan) and other derivatives of CPT have become a part of the multimillion dollar industry that is dedicated to finding better chemotherapeutic agents with excellent antitumor activity and less normal tissue toxicity. To achieve this goal, it is necessary to understand the details about the mechanisms of action, the targets of these drugs, and the cellular response to the drugs. Human topoisomerase I (topo I) relaxes superhelical tension associated with DNA replication, transcription and recombination by reversibly nicking one strand of duplex DNA and forming a covalent 3′-phosphotyrosine linkage. This enzyme is the sole target of the CPT family of anticancer compounds, which acts by stabilizing the covalent protein-DNA complex and enhancing apoptosis through blocking the advancement of replication forks. Once the CPT molecule has intercalated into the topo I-DNA cleavable complex, the collision between the complex and the replication fork during S-phase is thought to result in DNA double strand breaks (DSBs) that eventually lead to cell death.18,19 It has also been suggested that topo I cleaves DNA at multiple sites. The highest efficient sites exhibit significant sequence homology. Approximately 90% of topo I site have a tyrosine residue at position-1. However, sites of cleavage stabilized by CPT exhibit a strong preference for guanine at +1 position, while thymidine remains the preferred nucleobase at the -1 position.20 The exact mechanism by which CPT stabilizes the DNAtopo I covalent binary complex is not fully understood because the drug acts as an uncompetitive inhibitor and binds only the transient binary complex.21 Enzymology studies have revealed that CPT does not interact with topo I alone, nor does it bind to DNA.22 Although it has been reported that topotecan, which should be protonated at physiological pH, does bind to DNA at high concentration.23 Despite the * Phone: (909) 607-4249. Fax: (909) 607-7726. E-mail: rverma@ pomona.edu. Chem. Rev. 2009, 109, 213–235 213