# PREPARATION OF ADFRIAMYCIN ANALOGS & DERIVATIVES

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 1991 · $159,128

## Abstract

Treatment failure due to drug resistance remains a serious problem in
cancer therapy and a need continues to exist for new agents capable of
overcoming cellular drug resistance. Among clinical drugs, adriamycin
(doxorubicin), an anthracycline antibiotic, evidences the broadest
antitumor spectrum and is one of the most widely used agents in
chemotherapy. Yet a number of high-morbidity carcinomatous tumors are
intrinsically insensitive to its cytotoxic effects, while other tumors can
become resistant as a result of therapy with adriamycin or other cytotoxic
agents (pleiotropic or multidrug resistance). Recently we have identified
two exciting therapeutic leads, represented by hybrid
nitrosoureidoanthracyclines and novel lipophilic N-alkylanthracyclines, for
bypassing anthracycline and multidrug resistance. For each analogue-type,
prototype compounds have been found which are therapeutically superior to
adriamycin and less toxic in normally-responsive murine tumor model
systems, and which retain activity in one or more in vitro and/or in vivo
test systems normally exhibiting resistance to adriamycin cytotoxicity. The
present proposal seeks to conduct detailed systematic structure-activity
studies with these analogue-types in an attempt to identify optimally
active congeners for potential clinical evaluation against
adriamycin-resistant cancers. The specific objectives of this project are:
(1) to prepare key intermediates for the preparation of
structurally-modified N-alkylanthracyclines and nitrosoureidoanthracyclines
(these intermediates are often common to the derivation of both
analogue-type products); (2) to prepare various N-alkylanthracyclines
modified at the aglycone 4-position, the side-chain 14-position, and the
3'-amino and/or 4'-hydroxyl position of the parent anthracycline glycoside;
or in which the natural daunosamine glycoside is replaced by other
N-alkyl-substituted aminoglycoside functions; (3) to prepare similarly
modified nitrosoureidoanthracyclines, with special attention directed
towards products wherein an adjacent nitrosoureido and hydroxyl function
are in the more desirable trans geometric arrangement for enhanced chemical
stability; (4) to evaluate these target compounds in appropriate in vitro
growth inhibition and colony-formation assays and in vivo experimental
murine tumor assays to determine their biological activities and to provide
early indication of their ability to overcome resistance to adriamycin;
additionally, active products will be evaluated for their relative DNA
binding ability and potential for inhibition of nucleic acid synthesis,
factors which may provide early insight on their mechanistic effects; (5)
to provide samples of compounds of greatest interest to collaborating
investigators for biochemical studies relating to mechanisms of drug action
(alkaline elution assays, DNA unwinding assays, DNA topoisomerase II
inhibition assays, DNA crosslinking and repair of damage assays) and for
determination of acti...

## Key facts

- **NIH application ID:** 3174769
- **Project number:** 5R01CA037082-08
- **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:** 1991
- **Award amount:** $159,128
- **Award type:** 5
- **Project period:** 1983-07-01 → 1993-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174769

## Citation

> US National Institutes of Health, RePORTER application 3174769, PREPARATION OF ADFRIAMYCIN ANALOGS & DERIVATIVES (5R01CA037082-08). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174769. Licensed CC0.

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