David Bom

A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles

The power of radical reactions continues to increase! A cascade radical annulation route now allows perhaps the mildest and most general method for the synthesis of both known and new members of the camptothecin family (parent structure on the right) of antitumor agents.

7-silylcamptothecins (silatecans) : A new family of camptothecin antitumor agents

Abstract The synthesis and biological evaluation of about one dozen 7-silylcamptothecin derivatives are described. Most new compounds show potencies comparable to or better than camptothecin itself. The best compound, 11-fluoro-10-amino-7-trimethylsilylcamptothecin, is more than 20 times more potent than camptothecin in cell assays.

The cascade radical annulation approach to new analogues of camptothecins. Combinatorial synthesis of silatecans and homosilatecans.

Abstract: An overview of the cascade radical annulation approach to the camptothecin family of antitumor drugs is presented. This combinatorial synthetic approach involves two key steps: (1) N‐propargylation of a lactone/pyridone D/E ring fragment and (2) cascade radical annulation of an A‐ring isonitrile to form rings B and C. The synthesis is probably the most flexible and general route to the camptothecin class of molecules. The parallel synthesis of several libraries of silatecan and homosilatecan libraries is summarized. One of the first‐generation silatecans, DB‐67, is emerging as a serious candidate for cancer chemotherapy.

The combinatorial synthesis of racemic homosilatecan libraries via a cascade radical annulation.

Isolated from the Chinese tree, Camptotheca accuminata, in 1966 by Wani and Wall, camptothecin (CPT) has been a prominent lead for anticancer drug development for more than three decades. Despite its excellent in vitro activity, CPT failed in clinical trial because of its in vivo hydrolysis, which gives an inactive carboxylate.1–3 Susceptibility of the lactone functionality of CPT results from the intramolecular hydrogen bonding between the lactone carbonyl and the α-hydroxy group. However, this structural feature is needed for binding of CPT to the receptor. Thus, to have a stable lactone while maintaining activity remains a challenge in this field. Lipophilic CPT analogues were found to achieve lactone stabilization through lipid bilayer partitioning.4–6 Developed in our group, 7-silylcamptothecins (silatecans)7 were found to have highly improved blood stabilities, and one of them, DB67, was selected for preclinical development. Homocamptothecins, another class of E-ring analogues having a methylene spacer between the hydroxy and the carbonyl groups, were also found to have considerably improved blood stabilities.8 The combination of these two features resulted in homosilatecans that showed high lipophilicity and markedly improved human blood stabilities.9 We report here our synthesis of homosilatecan libraries for further structure-activity relationship studies. Synthesis of the racemic DE fragment is illustrated in Scheme 1. From commercially available starting material (1), intermediate (2) was prepared after five steps, and it was used in our synthesis of silatecan. Dihydroxylation followed by oxidative cleavage of the resulted diol gave ketone (3). Then, a Reformatsky reaction on ketone (3) followed by acid-catalyzed lactonization gave lactone (4). The TMS-iodide exchange was achieved using ICl as the iodination reagent. The reaction gave a high yield based on 50% recovery of the starting lactone (4). Finally, the methoxy group was deprotected by TMSI generated in situ to give the desired iodopyridone (6) (DE fragment) in 65% yield (Scheme 1). N-Alkylation of iodopyridone (6) with different propargyl bromides (7) gave compounds (8) that were subjected to a cascade radical annulation with different aryl isonitriles (9) to give racemic homosilatecans (10) with two elements of diversity (Scheme 2). More than 100 racemic homosilatecans (10) were prepared by this radical annulation reaction by either the traditional way or a Hewlett-Packard solution phase syn-

Fluorescence detection of camptothecin anticancer drugs by two-photon excitation

Hycamtin is a camptothecin anticancer analogue containing a dimethylaminomethyl substituent at position 9 and a hydroxy functionality at position 10. Using an excitation wavelength of 800 nm we have compared the two-photon cross sections and excited-state lifetimes from several camptothecins in phosphate buffered saline solution with and without the presence of human serum albumin (HSA). Drug and HSA concentrations of 10 (mu) M and 46 (mu) M were employed in our studies. In phosphate buffered saline solution containing HSA the following excited-state lifetimes (ns) and two- photon cross-sections (10-50 cm4 s/photon), respectively, were determined: hycamtin (4.3 nm, 36); camptothecin (1.3 ns, 1); 7-t-butyldimethylsilyl-10- hydroxycamptothecin (1.7 ns, 3.7); 7-t-butyldimethylsilyl- camptothecin (1.9 ns, 1.9); 7-trimethylsilyl-10- aminocamptothecin (6.3 ns; 35); and 7-trimethylsilyl-10- hydroxycamptothecin (1.8 ns; 2.2). Our results indicate that Hycamtin exhibits a high cross-section relative to the parent camptothecin molecule and represents one of the best camptothecin analogues to detect using two-photon excitation. Hycamtin was detected at concentrations as low as 0.05 (mu) M and 1 (mu) M in plasma and whole blood, respectively. The newly synthesized analogue 7- trimethylsilyl-10-aminocamptothecin was found to display similar lifetime and two-photon cross section values relative to Hycamtin. Thus, fluorescence detection with two- photon excitation may prove to be of advantage in the development of this promising new experimental therapeutic.

Applications of dynamic light scattering, fluorescence microscopy and fluorescence spectroscopy in DB-67 liposomal formulation studies

Campthothecin (CPT) and its analogues as prominent anticancer agents are currently the subject of the intensive studies. One of the most promising camptothecin analogues is 7-tert-butyldimethylsil- 1 0-hydroxycampthothecin called DB-67. It is characterized by high affinity to SUV (small unilamellar lipids vesicles) and relatively high stability in human blood. The studies of liposomal formulation as a delivery systems for DB-67 are the subject of this paper. The methods of dynamic light scattering (DLS), fluorescence microscopy (FM) and fluorescence spectroscopy (FS) are used to determine the physical properties of DB-67 liposomal formulation.