April 29, 1959

DOr. Joseph Lein, Director
Microbiological Research
Bristol Laboratorles Inc.
Syracuse |, New York

Dear Joe:
To yours of the 2hth.

Thank you for renewing your Invitation but while we have
sharply curtailed our trip to Europe, we st!!! have to be away
most of May and June. | know you are proud of your new labs and
will be more so of what comes out of them.

As to penicillins, It Is hard to suggest anything that Is
not obvious. You will be wanting to screen as quickly as possible
for resistance to penicl!linase and It would be difficult to
predict In advance what side graups would do this. The models
Suggest that It might just be possible to protect the lactam from
approaching the hydrolytic enzyme by substituting some very bulky
groups on the free amino position. Alternatively one might put
on some highly charged residues. Of course what these will do
to the antibacterial activity of the penicillin remains to be found.

Anything further on the preparation of phosphate-substituted
metabolites? My own hunch for the cancer problem is very strongly
in the direction of an analogue of RNA from tumor cells and the
main obstacle to testing this out may be achleving'its penetration
into the target cells.

I guess S.R.1. has been dragging its feet on our joint proposal
but | think they have had some personne! rearrangements that might
account for It. 1! do hope they come through.

Yours as ever,

Joshua Lederberg