Total synthesis and biological evaluation of fluorinated cryptophycins

Abstract

SummaryCryptophycins are cytotoxic natural products that exhibit considerable activities even against multi-drug-resistant tumor cell lines. As fluorinated pharmaceuticals have become more and more important during the past decades, fluorine-functionalized cryptophycins were synthesized and evaluated in cell-based cytotoxicity assays. The unit A trifluoromethyl-modified cryptophycin proved to be highly active against KB-3-1 cells and exhibited an IC50 value in the low picomolar range. However, the replacement of the 3-chloro-4-methoxyphenyl-substituent in unit B by a pentafluorophenyl moiety resulted in a significant loss of activity.

Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

“…For unit B, the retention of d -tyrosine and benzene ring bearing para -methoxy or ortho -hydroxy is necessary for the activity. Studies showed that the B segment bearing the 5-fluorine substituted benzene ring lost bioactivity [ 99 , 104 ]. The C fragment structure-activity studies have focused on the C6 position, and it has been determined that the introduction of a bulky substituent such as a benzyl or isopropyl group resulted in a considerable reduction of bioactivity, while geminal methyl groups or a cyclopropyl group in the C6 position enhanced anticancer activity.…”

Nonracemic γ‐Lactones from the Sharpless Asymmetric Dihydroxylation of β,γ‐Unsaturated Carboxylic Esters

“… “The product was obtained in enantiomerically pure form as shown by HPLC”, is stated in ref ,. but no numerical value is given.…”

“…The cytotoxic macrocyclic depsipeptide cryptophycin‐52 ( 300 , R = H) and its unnatural analogues 301a – d were synthesized in Scheme . The hydroxylactone motif ( 101 , 297a – d ) was established early on by the SAD strategy.…”

“…Total syntheses of cryptophycin‐52 ( 300 , R = H) and analogues ( 301a – d ) by Sewald et al (a) LDA, MeI, THF, –100 °C to –78 °C ( ds 100:0 in every case); (b) (MeO) 3 CH, pyridinium p ‐toluenesulfonate, CH 2 Cl 2 , room temp., 3 h; (c) AcBr, CH 2 Cl 2 , room temp., 5 h; (d) K 2 CO 3 (5 equiv), DME/ethylene glycol (2:1), room temp., 3 min.…”

Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting

“…Cryptophycin‐52 analogs with more than one fluorine substituent have recently been published (Figure ) . The CF 3 ‐functionalized compound is about fivefold less active against the tumor cell line KB‐3‐1 in comparison with cryptophycin‐52, while the pentafluorophenylalanine analog shows a significant loss of cytotoxicity, most likely owing to the absence of the methoxy group.…”