# THE DESIGN OF ANTITUMOR REDUCTIVE ALKYLATORS

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 1989 · $150,578

## Abstract

The proposal describes the rational design of antitumor agents by
exploiting biochemical differences between normal and tumor
cells.  Certain tumor cells possess high levels of the purine de
novo synthetic enzymes IMP dehydrogenase and adenylosuccinate
synthetase, as well as low reduction potential environment.  The
strategy is to design inhibitors directed towards these enzymes
which act only (or preferably) in this low potential environment.
A parallel effort will be to design crosslinkers of DNA that do
likewise.  The design to be employed for both cellular targets is
based on a class of naturally occurring quinones known as
reductive alkylators (e.g. mitomycin C, the saframycins, and the
anthracyclines).  These compounds become alkylators when
reduced to the hydroquinone form, presumably as a result of
quinone methide formation upon elimination of a leaving group.

Reductive alkylators based on the imidazo (4,5-g) quinazoline ring
system have been shown to mimick purine substrates in enzymatic
reactions as well as form an alkylating quinone methide species
upon reduction.  Thus, a reductive alkylator for xanthine oxidase
was designed which acts as a substrate in the oxidized form but
inactivates the enzyme upon reduction.  The proposed research
involves designing nucleotide reductive alkylators of the title
enzymes based on the imidazo(4,5-g) quinazoline ring system.
Another proposed area of study is the design of mechanistic
probes of the title enzymes employing this ring system.  This
aspect of the project will involve synthesis, enzyme kinetic
studies and antitumor screening.

Quinone methides based on the benzimidazole and quinazoline ring
systems have also been documented and found to be excellent
nucleophile traps.  It appears that the presence of nitrogen atoms
in the quinone methide favor nucleophilic addition over
electrophilic addition.  Effective alkylators of DNA may be
realized by replacing the indole nucleus of the mitosene form of
mitomycin C with benzimidazole and quinazoline.  The proposed
research involves the synthesis of the mitosene-like systems, DNA
crosslinking studies, and antitumor screening.  A DNA fragment
of defined sequence will be employed to investigate the site of
crosslinking.

## Key facts

- **NIH application ID:** 3174476
- **Project number:** 5R01CA036876-06
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **SAM.gov UEI:** NTLHJXM55KZ6
- **Principal Investigator:** EDWARD B SKIBO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $150,578
- **Award type:** 5
- **Project period:** 1984-05-01 → 1990-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174476

## Citation

> US National Institutes of Health, RePORTER application 3174476, THE DESIGN OF ANTITUMOR REDUCTIVE ALKYLATORS (5R01CA036876-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174476. Licensed CC0.

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