Water soluble 20(S)-glycinate esters of 10,11-methylenedioxycamptothecins are highly active against human breast cancer xenografts

Water-soluble 20(S)-glycinate esters of two highly patent 10,11-methylenedi oxy analogues of camptothecin (CPT) have been synthesized and evaluated for their ability to eradicate human breast cancer tumor xenografts, The glyci nate ester moiety increases the water solubility of the 10,11-methylenediox y analogues 4-16-fold. However, in contrast to CPT-11, a water-soluble CPT analogue that was recently approved for second line treatment of colorectal cancer, the 20(S)-glycinate eaters do not require carboxylesterase for con version to their active forms. The glycinate esters are hydrolyzed to their parent, free 20(S)-hydroxyl active analogues in phosphate buffer (pH 7.5) and in mouse and human plasma, The glycinate esters are also 20-40-fold les s potent than CPT-11 in inhibiting human acetylcholinesterase. In vivo, we examined 20(S)-glycinate-10,11-methylenedioxycamptothecin, 20(S)-glycinate- 7-chloromethyl-10,11-methylenedioxycamptothecin, and CPT-11. We found that the two 10,11-methylenedioxy analogues had antitumor activity against breas t cancer xenografts that was comparable to that of CPT-11. Our results indi cate that water-soluble 20(S)-glycinate eaters of highly potent CPT analogu es provide compounds that maintain biological activity, do not require inte ractions with carboxylesterases, and do not inhibit human acetylcholinester ase.