Synthesis of dolastatin 11 and analogs: Molecular modeling studies in this series

Abstract

The synthesis of dolastatin 11 was repeated on a much larger scale. Most of the yields and reaction conditions in the original synthesis were improved upon. Several problems that arose in the scale up were solved. The synthetic dolastatin 11 was obtained for the first time. The synthetic dolastatin 11 had good activity against a variety of cancer cell lines. The structure of the major by-product of the dolastatin 11 synthesis was determined. Several analogs of dolastatin 11 were synthesized. Testing results on the beta-alanine analog of dolastatin 11 showed it to have similar activity to the natural product. Molecular modeling studies on dolastatin 11 in both chloroform and water were pursued. The molecular modeling structure results in chloroform were consistent with NOE and coupling constant evidence. Molecular modeling calculations were also carried out on several dolastatin 11 analogs. These calculations combined with the testing results on dolastatin 11 and its beta-alanine analog indicate that the lowest energy conformation calculated for dolastatin 11 in chloroform may be the most active conformation.