Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20(S)-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents

Abstract

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

Design and synthesis of novel PEG-conjugated 20(S)-camptothecin sulfonylamidine derivatives with potent in vitro antitumor activity via Cu-catalyzed three-component reaction

“…Notably, the four most promising compounds 15 , 24 , 27 and 31 showed broad in vitro antitumor spectra and were about 10- to 150-fold more potent than 3 . Furthermore, similar to our previous results, 32 the cytotoxic potencies of these derivatives were dual controlled by altering the length of the sulfonylamidine arm as well as the size of the substituent group. The best antiproliferative activity was achieved only with an appropriate balance between flexibility and size, such as in 15 , 24 , 27 , and 31 .…”

“…32 Among them, some new compounds displayed potent antitumor activity with significantly different drug-resistance profiles from those of irinotecan ( 3 , Figure 1), a clinically available anticancer drug. In addition, they also were effective in drug-sensitive and drug-resistant xenograft models at lower doses than 3 , demonstrating potential as drug candidates for anticancer chemotherapy.…”

Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

“…Esterification of the 20-hydroxy group also enhances plasma stability and augments in vivo antitumor activity compared with unmodified 1 . In continuing these efforts, we recently reported that a series of 20-sulfonylamidine camptothecin derivatives displayed potent antitumor activity with significantly different drug-resistance profiles from those of 1 [20]. Among them, 9 was more active than 3 against the growth of A549, DU-145, KB, and KBvin with IC 50 values of 0.031, 0.050, 0.14 and 0.026 μM, respectively.…”

Molecular design, synthesis and biological research of novel pyridyl acridones as potent DNA-binding and apoptosis-inducing agents

“…A C C E P T E D ACCEPTED MANUSCRIPT 6 The synthesis of compounds 6a-w and 7a-c is shown in Scheme 1. First, compounds 3a-e were obtained from the Ullmann reaction of 2,4-dichlorobenzoic acid 2 with anthranilic acid 1a or its derivatives 1b-e in DMF using Cu as the catalyst [16,17].…”

“…While targeted anticancer drugs have been developed and clinically used, chemotherapy remains an important first-line treatment option for various cancers [2][3][4][5]. Therefore efforts have been continuously made for the development of more potent and less toxic anticancer chemotherapy drugs [6][7][8][9][10][11]. As part of the efforts in the discovery of potent antitumor agents, we have developed several series of new compounds such as aminopyrrolidine [12], tricyclic thiophene analogues [13] and acridine/acridone derivatives [14][15][16][17][18][19] with good antitumor activity.…”