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May 13-14, 2019 | Prague, Czech Republic
Chemistry and Medicinal Chemistry
9th World Congress on
Page 46
Asian Journal of Biomedical and Pharmaceutical Sciences | Volume 9 ISSN: 2249-622X
Sergey N Fedosov
Aarhus University, Denmark
Transport system of vitamin B12 (Cobalamin) in delivery of
therapeutic imaging B12-conjugates: Perspectives and problems
All animal cells need cobalamin (Cbl, vitamin B12),
because Cbl-cofactors are involved in synthesis of DNA
and membranes. The uptake of dietary Cbl by humans
starts with the binding to a Cbl-specific capturing protein
intrinsic factor, which facilitates the intestinal endocytosis.
The internalized Cbl is transferred to blood and binds to
the specific transporter transcobalamin, which delivers
Cbl to all tissues. The specific surface receptor (CD320)
renders the cellular uptake of transcobalamin–Cbl, and
the endocytosed vitamin is processed to its cofactors via
removal of a coordinated inactive group “X” from X– [Co 3+ ]
Cbl. The Cbl-transport system is a vehicle, which guarantees
a universal passage through cellular membranes for any
compound attached to Cbl, nearly irrespective of its size
and chemical features. Yet, modification of Cbl cannot be
done at an arbitrary place.
Thecrystallographicanalysisrevealedthestructuralelements,
where the attachment of external compounds gives the
lowest impact on Cbl-binding. A number of fluorescent and
radioactive Cbl-conjugates were used to visualize the main
target tissues (e.g. liver, kidney, tumors). Several toxic Cbl-
conjugates with an anti-cancer potential were also described
in the literature, but the parallel targeting of both malicious
and normal tissues would present a problem for patients.
Some alternative approaches are apparently required.
Attachmentofanon-removable“X”-group(in4-ethylphenyl–
[Co3+ ] Cbl) demonstrated that such compounds behave as
antagonists of Cbl, uselessly occupying the Cbl-transport
system but giving nearly no gain in the active cofactors.
Surprisingly, the tissue accumulation of the unprocessed
anti-vitamin was also relatively low, apparently because of
a continuous excretion of anti-Cbl from the cells. The overall
effect might result in Cbl-exhaustion of the fast propagating
cancer cells, combined with a low and revertible impact on
other tissues.
Electrochemical synthesis of DNA-Cbl conjugates opened
a potential to deliver therapeutic DNAs to the cells in vivo.
The internalized DNA-Cbl is expected to be split into DNA
and Cbl moieties, whereupon the antisense DNA would (i)
provoke enzymatic degradation of the target mRNA, and/or
(ii) block its translation. Malignant cells have distinct mRNA
patterns, implying a possibility of the targeted effect with a
low consequence for other tissues. Preliminary work with
the “nonsense” DNA-prototypes (suitable for easy tracking)
is discussed.
Speaker Biography
Sergey N Fedosov, Aarhus University, worked in different fields of science,
covering biochemistry & molecular biology, enzymology & catalysis, organic
& inorganic chemistry of cobalamin, synthesis of cobalamin derivatives and
adsorbents, computer modeling of metabolism, andmedical diagnostics. His
work was critical for a number of biotechnological companies, developing
pharmacological products. He is known in cobalamin community as inventor
of “Fedosov factor” (the combined index of B12 status). He is (co)author of
81 publications (+3 patents) with citations of >100 (5 publications), >50 (12
publications),andtheoverallauthor-metrics indexofh=28(GoogleScholar).
e:
Sergey N Fedosov, Asian J Biomed Pharmaceut Sci, Volume:9
DOI: 10.4066/2249-622X-C2-019
Notes: