Page 48 - Academic Press Encyclopedia of Physical Science and Technology 3rd InOrganic Chemistry

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Encyclopedia of Physical Science and Technology EN002F-55 May 22, 2001 21:6

136 Bioinorganic Chemistry

not used in therapy because these enzymes have a short the second-generation drug carboplatin are used in combi-
retention time in the body and do not cross cell mem- nation chemotherapy for treatment of lung, colorectal, and
branes efficiently. Therefore, bioinorganic chemists have ovarian cancers. Cisplatin is the most successful drug on
designed small molecules that can destroy superoxide and the market for testicular cancer. It is not understood why
are retained in the body and migrate into cells that are of cisplatin is so effective against testicular cancer while hav-
pharmacological significance. There are a few manganese ing little activity against tumors from many other organs.
complexes that have been shown to scavenge superoxide, Further study on platinum compounds focuses on us-
and research continues to develop effective superoxide ing different ligands to direct the platinum to different
dismutase mimics. In addition, a new class of manganese cells in efforts to attack different types of cancers. Other
porphyrins are being developed to destroy peroxynitrite. metal complexes show favorable ligand exchange proper-
One family of antitumorigenic compounds used in prac- ties and are being evaluated for their anticancer proper-
tice are the bleomycins, natural products that contain iron ties. Titanocene dichloride, a titanium(II) compound, is in
isolated from Streptomyces cultures. Bleomycin sulfate is clinical trials for action against gastrointestinal and breast
used in combination chemotherapy for treatment of head carcinomas. Compounds of ruthenium(III), known to bind
and neck cancer. The mechanism of action of bleomycin to DNA is much the same way as platinum, are also good
is believed to include the binding of oxygen to form candidates for anticancer drugs.
O 2 –Fe(II)–BLM. This complex can accept an electron to
2−
produce an active species, O –Fe(III)–BLM, which can D. Photophysical Properties
2
cleave DNA and RNA, ultimately killing the cancer cell.
Many inorganic compounds show unique properties upon
illumination. For example, some have very long excited
C. Metal Complexation in Medicine states due to the flipping of spin of the excited electrons.
To return to its preferred state, the electron spin must be
One mechanism of action for inorganic pharmaceuticals
flipped back to its original spin. Reaction with triplet oxy-
is the binding of the drug to a target biomolecule. A ligand
gen to produce singlet oxygen is one mechanism by which
already present on the metal must be lost in order to com-
this occurs. Singlet oxygen is cytotoxic, so if the metal
plex with the target. Inorganic compounds vary widely
complex can be targeted to a diseased area of the body,
in both thermodynamic driving force for their binding to
such as cancerous tissue, the complex can be illuminated
biomolecules and kinetic lability of the ligands present on
and singlet oxygen will result, damaging and, it is hoped,
them. This variability is useful in searching for drugs suffi-
destroying the disease. This mechanism is employed by
ciently stable to reach the targeted biomolecule, exchange
tin(IV) and lutetium compounds that are presently in clin-
ligands, and remain bound to the target until treatment is
ical trials. Porphyrins, when demetalated, can also be ex-
accomplished. The family of anticancer drugs is typified
cellent photosensitizers. These molecules can be directly
by cisplatin, a well-studied example of this mode of action.
photoactivated or be utilized in conjunction with radiation
Cisplatin is a neutral, square planar complex of plat-
therapy to increase the concentration of singlet oxygen in
inum(II). The mode of action of cisplatin is dependent on
tumor cells.
the lability of its chloride ligands. When cisplatin crosses
the cell membrane, the drug enters an environment that
E. Radiopharmaceuticals
is depleted of chloride ions. This causes the compound to
hydrolyze resulting in a charged complex that no longer Some inorganic isotopes such as 99m Tc and 186 Re decay ra-
can diffuse out of the cell. The positively charged drug is dioactively, giving off radiation (Table IV). This radiation
attracted to anionic DNA. At this point, bonds are made can then be detected using positron emission tomography
directly to the nucleobase guanine at the N7 site, the most (PET) or single-photon emission tomography (SPECT).
electron-rich site in nucleic acids. The major cisplatin Because the distribution of these molecules in the body
DNA adduct forms an intrastrand crosslink between ad- can be sensitively monitored, radiologists can use these
jacent guanines. The new complex is very stable and is metal complexes in applications ranging from blood flow
unlikely to undergo further ligand exchange. This DNA– monitoring to tumor detection. The ligands coordinating
Pt(II) adduct cannot be repaired by the cell. The resultant the isotope can be designed to direct the isotope for the
change in DNA structure is thought to block replication desired function.
through the modified region of the DNA. Whether this is For example, monoclonal antibodies (mAbs) attached
the correct mechanism for drug activity is unknown. Re- to isotopes can be directed toward cells that recognize
cent studies suggest that these regions may be responsible the specific antibodies. In one complex, indium-111 is
for binding high-mobility-group (HMG) proteins and in- attached to murine mAb B72.3, which is directed to an
activating them, resulting in loss of function of the proteins antigen expressed by many adenocarcinomas. In this way,
and ultimately death of the platinated cell. Cisplatin and the indium-111 will be retained in the location of the