Synthesis of an Alkyne‐Modified Bleomycin Disaccharide Precursor, Conversion to a ¹⁸F‐Labeled Radiotracer, and Preliminary in vivo‐PET Imaging Studies

Abstract

The bleomycins (BLMs) are known antitumor antibiotics composed of the tumoricidal and tumor seeking domains. The peptide structure of BLMs is responsible for the cytotoxicity by selective oxidative cleavage of DNA (and RNA), while the tumor cell selectivity and internalization resides in the disaccharide moiety (i.e. BLM disaccharide). This has prompted researchers to utilize BLM disaccharide and its derivatives as constituents for the selective recognition of tumor cells, which may find further applications as new tumor imaging tools or drug delivery vehicles. In the present study a high yielding synthesis of an alkyne modified BLM disaccharide precursor that may be used as a useful agent for the click conjugation, its conversion to a 18F‐labeled radiotracer, and preliminary in vivo PET imaging studies of the tracer with breast cancer (MCF‐7) xenograft mouse models are described.

Acetylene Group, Friend or Foe in Medicinal Chemistry

“…Positron emission tomography (PET) Maity and co-workers synthesized an alkyne-containing bleomycin disaccharide devoid of peptide domain that will be click conjugated with 18 F-labeled radiotracer to obtain and study PET imaging of 180 in vivo in a breast cancer xenograft mouse model (Figure 79). 212 The results, however, indicated poor uptake of 180 into the tumor but high uptake in the kidneys, thus suggesting the role of a peptide domain of bleomycin toward overall uptake profile. Clickable Antihuman PD-L1 Adnectin for in Vivo PET Imaging.…”

Assembly of Bleomycin Saccharide-Decorated Spherical Nucleic Acids

“…For the synthesis of azide-modified bleomycin disaccharide precursors 3α and 3β ( Scheme 1 ), the previously reported 2- O -[2,4,6-tri- O -acetyl-3- O -( p -nitrophenylformyl)-α- d -mannopyranosyl]-3,4-di- O -benzoyl-6- O -acetyl- l -gulopyranose ( 1 ) 44 was glycosylated with 2-(2-azidoethoxy)ethanol using in situ formation of a sulfoxide donor in the presence of trifluoromethanesulfonic anhydride, diphenyl sulfoxide, and 2,4,6-tri- tert -butyl pyridine. Compound 2 was obtained as pure α- and β-anomers in 48 and 32% yields, respectively (overall yield 80%).…”

“…The carbamoyl mannose moiety alone also mediates selective tumor cell targeting . Furthermore, clusters consisting of bleomycin disaccharide or carbamoyl mannose units are taken up by cells more efficiently, indicating that the binding of bleomycin disaccharide to cell surface receptors is multivalent. ,, Hence, the bleomycin saccharides may be potential targeting agents that would deliver oligonucleotide payloads to cancer cells, , but the efficient enough targeting may need high multivalency.…”

Solvent-Free Approaches in Carbohydrate Synthetic Chemistry: Role of Catalysis in Reactivity and Selectivity

“…It is pertinent to specify at this stage that some tin-catalyzed approaches in solution have appeared after the described report on the solvent-free conditions, with considerable simplification over the traditional stepwise stoichiometric method [48][49][50][51][52]. It is also worth observing that solvent-free benzylation protocols described herein have already been incorporated into a variety of synthetic projects [53][54][55][56], to testify their practical scope.…”