# DELIVERY OF ANTI-PROLIFERATIVE AGENTS THROUGH SKIN

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 1987 · $57,426

## Abstract

The reason that many anti-proliferative agents are effective orally but not
topically in the treatment of psoriasis may be that they do not diffuse
through skin to a sufficient extent to generate a clinically beneficial
response.  In order to test this hypothesis the synthesis and testing in
animals of new types of S- and N- alkylated derivatives (prodrugs) of one
member of the orally active, topically ineffective anti-proliferative
agents (6-mercaptopurine (6-MP) and its riboside) is proposed.  The
prodrugs are designed to increase the delivery of 6-MP through skin.  They
are hydrolytically reversible derivatives that do not require any initial
oxidative step to make them labile, and in that sense they may be
considered as soft alkylated derivatives.  Generally the soft alkylated
derivatives of 6-MP have the formula RCOXCHR'X'-drug where X=N or O; X'=N
or S; R is aryl, alkyl, alkoxy or alkylamino; and R' is hydrogen or an
electron withdrawing functional group.  Representative S-pivalyloxymethyl
and N-methyl-N-carboethoxyaminomethyl derivatives of 6-MP and 6-MP riboside
have been synthesized and characterized in terms of their hydrolysis rates,
partition coefficients and ability to deliver 6-MP through skin in
diffusion cell experiments.  These soft alkylated derivatives regenerate
6-MP in vivo and have been found to increase the delivery of 6-MP across
hairless mouse skin by 3 to 12 times.  It is proposed that 1) the present
derivatives be tested on hairless mice to determine if the derivatives
inhibit DNA synthesis in hairless mice - an animal model that correlates
well with topical clinical efficacy in man; 2) if the present derivatives
are active, the rate of delivery of 6-MP be maximized by adjusting the R,
X, X' and R' groups in the general formula to obtain the most favorable
partition coefficient, diffusivity, and rate of regeneration of 6-MP for
the derivatives; and 3) the best derivatives in terms of ability to deliver
6-MP be tested for inhibition of DNA synthesis in hairless mice.  Thus,
whether 6-MP is topically inactive or merely not enough 6-MP is getting
through skin to be effective will be established in an animal
model-hairless mice-that correlates with topical clinical efficacy in man.
In addition, a potentially useful general approach (soft alkylated thiols
and amines) to improving topical delivery and efficacy of
anti-proliferative drugs will be optimized for one example, 6-MP.

## Key facts

- **NIH application ID:** 3156695
- **Project number:** 5R01AR033957-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **SAM.gov UEI:** NNFQH1JAPEP3
- **Principal Investigator:** KENNETH B SLOAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $57,426
- **Award type:** 5
- **Project period:** 1985-04-01 → 1989-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156695

## Citation

> US National Institutes of Health, RePORTER application 3156695, DELIVERY OF ANTI-PROLIFERATIVE AGENTS THROUGH SKIN (5R01AR033957-03). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3156695. Licensed CC0.

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