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20 June 1992

Science: Molecular machine springs trap for cancer cells

Anticancer molecule and DNA

Molecules which can selectively invade cancer cells and tear their DNA
to shreds have been made by chemists in California. They have been developed
by modifiying a natural antibiotic of a type called an enediyne (pronounced
‘een-di-ine’). Once inside a cancer cell, the modified molecules can change
into destructive ‘free radicals’ and kill the cell.

‘Designer’ enediynes have been made by K. C. Nicolaou and his colleagues
at the Scripps Research Institute in La Jolla, California. Preliminary tests
showed that they were more potent than anticancer drugs such as cis-platin,
doxorubicin, bleomycin and taxol, a recently discovered extract from yew
the tree (Science, vol 256, p 1172).

An enediyne is a chain of six carbon atoms linked by two triple bonds
and one double bond. With a little encouragement, this chain of atoms can
rearrange itself into a benzene ring with two hydrogen atoms missing (see
Diagram). This acts as a free radical, and will scavenge the missing hydrogen
atoms from any molecule near at hand, an action which is particularly effective
if the nearby molecule is DNA, because DNA has some loosely held hydrogen
atoms. DNA’s hydrogen atoms play an essential to part in holding its strands
together, so when it loses some of them it falls apart.

Nicolaou’s team built an enediyne fragment into a molecule with other
groups so that it can seek out cancer cells, invade them and, once locked
onto their DNA, transform itself into a free radical. The chemists achieved
this feat by attaching to the enediyne core chemical groups, which Nicolaou
calls ‘detectors’, ‘deactivators’, ‘tetherers’ and ‘initators’. The detector
groups enable the chemists to track the molecule within a cell.


Natural enediynes were first identified in 1985 by Kiyoto Edo and his
colleagues at Tohoku University Hospital, Japan. The first one, dubbed
neocarzinostatin chromophore, was extracted from neocarzinostatin, a polypeptide
known to have anticancer activity. In all these compounds, the enediyne
unit is part of a much larger molecule. What Nicolaou’s team has done is
to stabilise the enediyne by anchoring it to a rigid double ring to which
other groups are attached.

So far, the Californian chemists have made 11 designer enediynes, which
are stable and inactive in neutral or acidic surroundings. Only under basic
conditions do they become destructive.

In tests, the compounds tended to ignore normal cells, but they invaded
tumour cells. A large percentage of the genetic material of invaded cells
was damaged, even before death of the cell, showing that DNA was the primary
target of the enediyne. The compounds were particularly effective against
leukaemia. Tests on animal showed that the designer enediynes were less
toxic than the natural enediynes.

Nicolaou based his designer molecules on the natural molecule dynemicin-A,
which has an oxygen bridge (epoxide) between a pair of neighbouring atoms
at the centre of the rings to which the enediyne is attached, and which
has a nitrogen atom as part of one of the rings. It is through the epoxide
and the nitrogen atom that the molecule can be controlled and activated;
the epoxide is the trigger, and the nitrogen atom is the safety catch.

More specifically, it is the pair of free electrons on the nitrogen
atom which must be held in check to prevent the molecule going into action.
The chemists achieve this by attaching an ‘initiator’ group to the nitrogen
which keeps the safety catch in place while the molecule is in acid or neutral
conditions. But in basic surroundings the group immediately detaches itself,
freeing the nitrogen’s electron pair to move towards the oxygen bridge,
which breaks. The whole molecule now ‘relaxes’, decreasing the separation
of the carbon atoms of the triple bonds by 50 picometres – enough to enable
them to form the hydrogen-deficient benzene ring, with its free radical
sites, to attack any DNA that happens to be nearby.

Nicolaou tested his enediynes against a broad spectrum of cancers, and
showed that changes to the group attached to the nitrogen atoms could increase
the potency of the drug by up to 10 000 times.