# ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 1987 · $155,977

## Abstract

The activity of inhibitors of dihydrofolate reductase (such as
methotrexate) as cancer chemotherapeutic agents has led to the search for
alternate target enzyme within the folate pathways that are essential for
proliferating cells.  Folylpolyglutamate synthetase has these
characteristics and is being examined as a new target for folate
antimetabolites.  Previous studies have indicated that interaction of the
glutamic acid side chain of the folate molecule is essential for binding of
folate analogs bind poorly to folylpolyglutamate synthetase, a fact that
indicates rigid structural requirements in the active site of this enzyme.
One class of compounds, however, that are modified in the Omega-position
have been found to be the first specific inhibitors of this enzyme.  The
overall goals of this work are to exploit this lead for the procurement of
a potent inhibitor of folylpolyglutamate synthetase in tumor cells.
Several new classes of folate analogs will be synthesized.  The side chains
of these compounds will differ from glutamic acid by modifications that
will allow the testing of a number of hypotheses related to interactions
between substrates and enzyme.  We would modify the folate structure so as
to :  1) alter the pKa of the Alpha- or Gamma-carboxyls; 2) allow the
alkylation of any basic amino acid interacting with the Alpha-carboxyl of
the folate substrate; 3) increase the binding of homocysteic acid analogs
to enzymes; 4) replace the Alpha- or Gamma-carbosyls with other charged
moieties; and 5) eliminate the Alpha- or Gamma-carboxyl in any analog that
bound tightly to enzyme.  These compounds will be studied as inhibitors of
polyglutamation using partially purified mammalian folylpolyglutamate
synthetase and also in intact mammalian tumor cells in culture.  A compound
that inhibits this process will be used to select for resistant cell
lines.  The cytotoxicity of new analogs will be tested against tumor cells
in culture and in vivo.

## Key facts

- **NIH application ID:** 3179001
- **Project number:** 5R01CA039687-03
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **SAM.gov UEI:** DVL1CMRMWRN9
- **Principal Investigator:** RICHARD G MORAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $155,977
- **Award type:** 5
- **Project period:** 1985-09-30 → 1988-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3179001

## Citation

> US National Institutes of Health, RePORTER application 3179001, ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE (5R01CA039687-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3179001. Licensed CC0.

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