In Silico Rationalization of Progesterone Prodrugs’ Self-Immolation Rate Open Access
Yeung, Sean (Spring 2025)
Abstract
In the United States, traumatic brain injury is the most common cause of death for men under 35. Yet, there remains no FDA-approved therapeutic intervention for TBI. While the natural steroid progesterone proves a promising candidate to address TBI, its hydrophobicity limits its practicality and functionality. Prior attempts to increase steroid solubility via a pH-dependent carbamate prodrug have resulted in either undesirable storage stability or parental release rate. Thus, in this work, we aim to discover Goldilocks compounds for storage stability and parental release rate. Towards this goal, carbamate rotamer control was employed.
The Liotta research group synthesized a library employing two syn-selecting design strategies, steric clash and electronic tethering, prior to empirically evaluating their self-immolation rates, which correspond with elimination of a parent progesterone analogue. My consequent in silico analysis robustly supports that the concentration of the carbamate promoiety in the syn-conformer correlates with the rate of self-immolation. For the steric clash series, research described herein revealed that β sterics predominated overall sterics in predicting anti-destabilization and rate of prodrug self-immolation. For the electronic tether series, we have revealed that pKa of the tertiary amine is an important factor, and in silico results suggest a pKa-mediated syn-stabilizing hydrogen bonding interaction driving the rate of prodrug self-immolation.
Overall, we have tuned pH-dependent carbamate prodrugs via syn-selecting substituents, successfully elucidating several compounds falling within a Goldilocks zone between storage stability in acidic conditions and rapid release of the upon a change to physiological pH. The Liotta research group synthesized a library employing two syn-selecting design strategies, steric clash and electronic tethering, prior to empirically evaluating their self-immolation rates, which correspond with elimination of a parent progesterone analogue. My consequent in silico analysis robustly supports that the concentration of the carbamate promoiety in the syn-conformer correlates with the rate of self-immolation. For the steric clash series, research described herein revealed that β sterics predominated overall sterics in predicting anti destabilization and rate of prodrug self-immolation. For the electronic tether series, we have revealed that pKa of the tertiary amine is an important factor, and in silico results suggest a pKa-mediated syn-stabilizing hydrogen bonding interaction driving the rate of prodrug self-immolation.
Overall, we have tuned pH-dependent carbamate prodrugs via syn-selecting substituents, successfully elucidating several compounds falling within a Goldilocks zone between storage stability in acidic conditions and rapid release of the upon a change to physiological pH.
Table of Contents
Introduction.……………………………………………………………………………………….1
Results and Discussion………………………………………….……………………………….12
Conclusion…………………………………………………………………...………….……….22
Experimental Procedures……………………………………………………….…………….….23
References………………………………………………………………………………………. 25
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In Silico Rationalization of Progesterone Prodrugs’ Self-Immolation Rate () | 2025-04-28 10:15:08 -0400 |
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