# PHARMACOLOGIC EVALUATION OF NEW ADRIAMYCIN ANALOGS

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 1988 · $181,193

## Abstract

The anthracycline antitumor antibiotic adriamycin (doxorubicin)
continues to be one of the most widely used drugs in cancer
medicine.  However, its toxicity and lack of effectiveness against
some of the more common carcinomatous tumors continue to emphasize
a need for analogs with improved therapeutic efficacy.  While
others approached this work from the generally-accepted mechanistic
aspect of drug-DNA binding, work in these laboratories included the
study of analogs having greatly altered capacity for DNA binding.
This unconventional approach has resulted in the development of
some of the most active and mechanistically-novel adriamycin
analogs so far developed for clinical evaluation.  One analog, N-
trifluoroacetyladriamycin-14-valerate (AD 32), for which no
interaction with DNA has yet been demonstrated, has already shown
activity in humans, with low toxicity in general and no
cardiotoxicity in specific; N-trifluoroacetyladriamycin-14-0-
hemiadipate (AD 143), a second-generation AD 32 analog with
improved aqueous solubility, is about to enter the clinic.  We have
now identified a new family of promising 14-acyl-N-alkyladriamycin
analogs which show therapeutic superiority to adriamycin and,
surprisingly, to the corresponding N-alkyl analogs lacking the 14-
acyl substituent.  In addition, these products, as typified by N-
benzyladria-mycin-14-valerate (AD 198), show a range of mechanistic
properties quite different from those of adriamycin or the N=acyl
AD 32/AD 143-type compounds.  The present proposal is concerned
with preclinical developmental studies with these new N-alkyl-
anthracycline analogs in order to better define their antitumor
activity, toxicity, and pharmacology.  In addition, the preparation
and evaluation of similar 4-O-desmethyl-N-alkylanthracycline
analogs will be conducted, based upon the finding of unusually high
levels of 4-0-desmethylated metabolites in animals treated with AD
198.  Further pharmacologic studies with AD 32 and AD 143, aimed
at improving the potential clinical efficacy of these agents, are
included.  In addition, the resources provided by this program will
be used for the early evaluation of other new and mechanistically
novel adriamycin analogs emerging from our parallel drug synthesis
effort: the results of these studies will thus provide a basis for
the selection of future target compounds for eventual detailed
investigation.

## Key facts

- **NIH application ID:** 3175003
- **Project number:** 2R01CA037209-03A3
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **SAM.gov UEI:** X1M1PN3KG3E7
- **Principal Investigator:** MERVYN ISRAEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $181,193
- **Award type:** 2
- **Project period:** 1983-07-01 → 1992-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175003

## Citation

> US National Institutes of Health, RePORTER application 3175003, PHARMACOLOGIC EVALUATION OF NEW ADRIAMYCIN ANALOGS (2R01CA037209-03A3). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175003. Licensed CC0.

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