[151]. The products have been obtained in moderate to excellent isolated yields
with good chemo- and stereoselectivities. These results are all the more remarkable
given that in optimized conditions the percentages of undesired Meyer–Schuster or
O-allylation products are very low, while they are majority products when V or Pd
catalyst are taken alone. The mechanism proposed by Trost for this reaction
involves as key step the coupling of a vanadium allenoate and a π-allylpalladium
intermediate, the rate of this bimolecular coupling being much faster than the
competitive protonation or O-alkylation of the intermediates.
5 Early–Late Heterobimetallic Complexes as New
Anticancer Agents
In this chapter, the interests of gathering an early metal with a late one were clearly
put forward concerning the field of catalysis. Catalysis is not the only field using
metals. Indeed, they are widely used in medicine as for treating stomach ulcers
(bismuth) [152], diabetes (vanadium) [153], rheumatoid arthritis (gold) [154],
cancer (platinum and others) [155], etc. As a consequence, early–late heterobimetallic complexes seem to be interesting objects to be investigated for their
biological properties. Surprisingly, as far as we are aware, only two research groups
published significant results on this subject [91, 156, 157, 158, 159]. The reasons
may be the reputed instability of the early metal complexes in aqueous media.
Indeed, for biological applications the compound should be stable enough in
physiological media to reach its target.
Today, the only early metal integrated in heterobimetallic complexes for anticancer purposes is titanium. That might be explained considering that titanocene
dichloride was the first organometallic complex which entered clinical trials in 1993
[160]. Its activity in vitro and in vivo in experimental models was really promising
[161, 162] even in tumors difficult to treat [163]. Unfortunately, due to its lack of
efficacy in patients, [Cp 2 TiCl 2 ] did not fulfill the criteria required in phase II clinical
trials. To tackle this problem, some researchers as Tacke [164] or Tshuva [165]
designed specific titanium complexes which gave very promising results. Our group
and Maria Contel’s one chose another strategy: adding at least one late metal.
Obviously, the choice of the second metal was made in the most promising metals
in oncology: platinum, ruthenium, and gold [166]. Indeed, nowadays cisplatin and
platinum derivatives are used in clinics in more than 50% of anticancer chemotherapeutic cocktails [167]. Several ruthenium complexes entered clinical trials such as
NAMI-A, KP1019, or NKP1339. Concerning gold derivatives, two drugs used previously for rheumatoid arthritis – auranofin and sodium aurothiomalate – are now
investigated in clinical trials for the treatment of cancer. Titanium and platinum are
thought to enter nucleus of the cell and target DNA or chromatin, while most of
ruthenium and gold complexes seem to accumulate in the cytoplasm and target
“Early–Late” Heterobimetallic Catalysis and Beyond
179
with good chemo- and stereoselectivities. These results are all the more remarkable
given that in optimized conditions the percentages of undesired Meyer–Schuster or
O-allylation products are very low, while they are majority products when V or Pd
catalyst are taken alone. The mechanism proposed by Trost for this reaction
involves as key step the coupling of a vanadium allenoate and a π-allylpalladium
intermediate, the rate of this bimolecular coupling being much faster than the
competitive protonation or O-alkylation of the intermediates.
5 Early–Late Heterobimetallic Complexes as New
Anticancer Agents
In this chapter, the interests of gathering an early metal with a late one were clearly
put forward concerning the field of catalysis. Catalysis is not the only field using
metals. Indeed, they are widely used in medicine as for treating stomach ulcers
(bismuth) [152], diabetes (vanadium) [153], rheumatoid arthritis (gold) [154],
cancer (platinum and others) [155], etc. As a consequence, early–late heterobimetallic complexes seem to be interesting objects to be investigated for their
biological properties. Surprisingly, as far as we are aware, only two research groups
published significant results on this subject [91, 156, 157, 158, 159]. The reasons
may be the reputed instability of the early metal complexes in aqueous media.
Indeed, for biological applications the compound should be stable enough in
physiological media to reach its target.
Today, the only early metal integrated in heterobimetallic complexes for anticancer purposes is titanium. That might be explained considering that titanocene
dichloride was the first organometallic complex which entered clinical trials in 1993
[160]. Its activity in vitro and in vivo in experimental models was really promising
[161, 162] even in tumors difficult to treat [163]. Unfortunately, due to its lack of
efficacy in patients, [Cp 2 TiCl 2 ] did not fulfill the criteria required in phase II clinical
trials. To tackle this problem, some researchers as Tacke [164] or Tshuva [165]
designed specific titanium complexes which gave very promising results. Our group
and Maria Contel’s one chose another strategy: adding at least one late metal.
Obviously, the choice of the second metal was made in the most promising metals
in oncology: platinum, ruthenium, and gold [166]. Indeed, nowadays cisplatin and
platinum derivatives are used in clinics in more than 50% of anticancer chemotherapeutic cocktails [167]. Several ruthenium complexes entered clinical trials such as
NAMI-A, KP1019, or NKP1339. Concerning gold derivatives, two drugs used previously for rheumatoid arthritis – auranofin and sodium aurothiomalate – are now
investigated in clinical trials for the treatment of cancer. Titanium and platinum are
thought to enter nucleus of the cell and target DNA or chromatin, while most of
ruthenium and gold complexes seem to accumulate in the cytoplasm and target
“Early–Late” Heterobimetallic Catalysis and Beyond
179