The key to fighting breast cancer may lie in an almost forgotten physical chemistry concept from the 1920s.
In the relentless battle against hormone-dependent breast cancer, scientists continually search for new strategies to disarm the enemy. For decades, the focus has been on developing drugs that block estrogen production or action—the fuel that feeds approximately 70-80% of breast cancers3 .
An obscure physical chemistry measurement from the 1920s is helping researchers design more effective aromatase inhibitors, the vital drugs that starve estrogen-dependent cancer cells of their fuel.
Meanwhile, in the archives of physical chemistry, an almost forgotten concept called "parachor" has emerged as an unexpected ally in this fight. Originally developed in the 1920s to study molecular volumes and surface tensions, parachor has found a surprising new application: helping researchers design more effective aromatase inhibitors. This is the story of how an obscure physical chemistry measurement is helping rewrite the future of cancer treatment.
Parachor is a physical chemistry concept introduced by scientist S. Sugden in 1924 that relates surface tension to molecular volume and composition1 5 . The term combines "para-" (meaning "aside") and "-chor" (from Greek meaning "space")1 .
P = γ1/4 M / (ρL - ρV)
Surface tension
Molecular weight
Liquid density
Vapor density
In simpler terms, parachor represents an empirical constant that allows scientists to compare molecular volumes under conditions where liquids have identical surface tensions5 . What makes parachor particularly valuable is that it can be calculated by adding specific values assigned to constituent atoms and structural features of a molecule5 9 .
| Atom/Group | Sugden's Value (1924) | Quayle's Value (1953) |
|---|---|---|
| -CH₂- | 39.0 | 40.0 |
| -H | 17.1 | 15.5 |
| -O- | 20.0 | 19.8 |
| -Cl | 54.3 | 55.2 |
| Double bond | 23.2 | 16.3-19.1 |
| Six-membered ring | 6.1 | 0.8 |
To understand parachor's role in drug development, we must first grasp the enemy it's helping to fight.
Aromatase (also known as CYP19A1) is a crucial enzyme in estrogen biosynthesis3 . It catalyzes the conversion of C19 androgens—including androstenedione and testosterone—into C18 estrogens such as estrone and estradiol3 . This process, known as aromatization, occurs primarily in the ovaries of premenopausal women and in peripheral tissues (like adipose tissue) in postmenopausal women3 .
Accounts for approximately 70-80% of all breast cancer cases3
In estrogen receptor-positive (ER+) breast cancer, tumor growth is fueled by estrogen. Aromatase inhibitors (AIs) work by blocking the aromatase enzyme, effectively reducing estrogen levels in the body and thereby depriving cancer cells of the hormonal stimulation they need to grow and multiply3 4 .
Non-steroidal aromatase inhibitor
Non-steroidal aromatase inhibitor
Steroidal aromatase inhibitor
These drugs have become cornerstone treatments for postmenopausal women with ER+ breast cancer, both in early-stage disease (to prevent recurrence) and advanced settings3 4 .
The intersection of parachor and aromatase inhibitor development represents a fascinating example of cross-disciplinary innovation in science.
The field of QSAR relies on establishing mathematical relationships between the chemical structure of compounds and their biological activity. By quantifying structural features, researchers can predict which molecules are likely to have potent therapeutic effects.
Parachor serves as an excellent steric parameter in QSAR studies because it provides information about molecular volume and spatial requirements—critical factors in drug-receptor interactions2 6 . When a drug molecule fits perfectly into its target enzyme (like a key in a lock), its steric properties significantly influence how tightly it binds.
In 1990, a landmark French study explored the contribution of parachor to the structure-activity relationship of androstenedione derivatives as aromatase inhibitors2 . The researchers investigated how modifications to the androstenedione structure affected the compounds' ability to inhibit aromatase.
| Research Phase | Methodology | Purpose |
|---|---|---|
| Compound Synthesis | Chemical modification of androstenedione structure | Create derivatives with varied steric properties |
| Parachor Calculation | Using group contribution values | Quantify molecular volume and spatial properties |
| Activity Testing | In vitro aromatase inhibition assays | Measure biological effectiveness of each derivative |
| Correlation Analysis | Statistical analysis of parachor vs. inhibition | Establish structure-activity relationships |
The study focused on androstenediones—steroid compounds that serve as the natural substrate for the aromatase enzyme. By chemically modifying these molecules, scientists can transform them from substrates (which the enzyme converts to estrogen) into inhibitors (which block the enzyme's activity).
Researchers created various derivatives of androstenedione with modified structural features to test how different molecular volumes affected aromatase inhibition.
Using established group contribution values, parachor was calculated for each derivative to quantify molecular volume and spatial properties.
Each compound was tested in vitro for its ability to inhibit aromatase enzyme activity, measuring biological effectiveness.
The findings revealed significant correlations between parachor values and inhibitory potency for two distinct classes of steroid inhibitors of estrogen biosynthesis2 6 .
"Good correlations were obtained for two classes of steroids inhibitors of oestrogens biosynthesis" - French Study, 19902
This relationship makes intuitive sense when we consider that the active site of aromatase—where the inhibitor must bind—has very restrictive spatial requirements. Research has shown that the enzyme permits only small structural changes to be made on the A-ring and at the C-19 position of steroid molecules.
| Compound Code | Chemical Modifications | Anti-aromatase Activity | Additional Targets |
|---|---|---|---|
| 6 (7α-methylandrost-4-en-17-one) | Modification in A- and B-rings | 97.39% inhibition | Androgen receptor agonist, ER modulator |
| 10a (7α-methylandrost-4-ene-3,17-dione) | Modification in B-ring | 94.35% inhibition | Androgen receptor agonist, ER modulator |
| 13 (androsta-4,9(11)-diene-3,17-dione) | Modification in C-ring | 95.22% inhibition | Androgen receptor agonist, ER modulator |
The future of aromatase inhibitor development is moving toward polypharmacology—the design of single drugs that can hit multiple targets simultaneously8 . This approach recognizes the complexity of cancer biology and the limitations of single-target strategies.
Recent advances include steroidal AIs that not only inhibit aromatase but also modulate estrogen receptors and act as androgen receptor agonists8 . This multi-target action provides a therapeutic advantage by addressing complementary pathways in cancer growth and potentially delaying or preventing resistance development8 .
The story of parachor in aromatase inhibitor research reminds us that scientific progress often bridges disparate fields. What began as a simple method to relate surface tension to molecular volume in the 1920s has evolved into a valuable tool for designing life-saving cancer therapies.
As research continues to advance, with multi-target inhibitors and personalized treatment approaches on the horizon, the quiet contribution of parachor to understanding molecular structure-activity relationships continues to resonate through laboratories and clinics worldwide. In the intricate dance of drug discovery, sometimes the oldest steps inform the newest breakthroughs.