Details
| Original language | English |
|---|---|
| Article number | e01965 |
| Journal | Chemistry - a European journal |
| Volume | 31 |
| Issue number | 46 |
| Publication status | Published - 19 Aug 2025 |
Abstract
Tubulysins belong to a class of natural products originally isolated from myxobacteria culture and are known to induce cell apoptosis through inhibition of microtubule assembly. Herein, we report the computationally designed, structurally simplified, and first solid-phase peptide synthesis of novel third-generation tubulin inhibitors in high yields. These inhibitors are devoid of tubuvaline and tubuphenylalanine fragments previously considered essential for tubulin inhibition activity. The most potent inhibitor contains four fragments arranged from the N terminal to the C terminal as N-methyl pipecolic acid, isoleucine, valine-thiazole, and asparagine. The hydrophilic tubulin inhibitors demonstrated significant anticancer activity, with IC50 values in the low nanomolar range (IC50 = 13–53 nM) within a 48 hours incubation period across prostate, lung, breast, skin, and cervical cancer cell lines. The synthetic strategy incorporates a simplified valine-thiazole ring structure, retaining both biological activity and chiral integrity of the molecules. The method enables the synthesis of potent tubulin inhibitors by avoiding multistep synthetic and purification procedures, supporting the inhibitor's applicability for large-scale synthesis and potential therapeutic development. The structural modifications at the N-terminal result in the loss of activity from nM to µM range, whereas the C-terminal modification had minimal impact on the potency.
Keywords
- anticancer, computational design, microtubule, solid-phase peptide synthesis, tubulin inhibitor, tubulysin
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- General Chemistry
- Chemistry(all)
- Organic Chemistry
Sustainable Development Goals
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In: Chemistry - a European journal, Vol. 31, No. 46, e01965, 19.08.2025.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Design, Synthesis, and Cytotoxic Evaluation of New Structurally Simplified and Highly Potent Third-Generation Tubulysin Derivatives
AU - Yadav, Kratika
AU - Kalita, Tapash
AU - Sharma, Lekhnath
AU - Pandit, Amit
AU - Pathak, Biswarup
AU - Dräger, Gerald
AU - Kirschning, Andreas
AU - Chelvam, Venkatesh
N1 - Publisher Copyright: © 2025 Wiley-VCH GmbH.
PY - 2025/8/19
Y1 - 2025/8/19
N2 - Tubulysins belong to a class of natural products originally isolated from myxobacteria culture and are known to induce cell apoptosis through inhibition of microtubule assembly. Herein, we report the computationally designed, structurally simplified, and first solid-phase peptide synthesis of novel third-generation tubulin inhibitors in high yields. These inhibitors are devoid of tubuvaline and tubuphenylalanine fragments previously considered essential for tubulin inhibition activity. The most potent inhibitor contains four fragments arranged from the N terminal to the C terminal as N-methyl pipecolic acid, isoleucine, valine-thiazole, and asparagine. The hydrophilic tubulin inhibitors demonstrated significant anticancer activity, with IC50 values in the low nanomolar range (IC50 = 13–53 nM) within a 48 hours incubation period across prostate, lung, breast, skin, and cervical cancer cell lines. The synthetic strategy incorporates a simplified valine-thiazole ring structure, retaining both biological activity and chiral integrity of the molecules. The method enables the synthesis of potent tubulin inhibitors by avoiding multistep synthetic and purification procedures, supporting the inhibitor's applicability for large-scale synthesis and potential therapeutic development. The structural modifications at the N-terminal result in the loss of activity from nM to µM range, whereas the C-terminal modification had minimal impact on the potency.
AB - Tubulysins belong to a class of natural products originally isolated from myxobacteria culture and are known to induce cell apoptosis through inhibition of microtubule assembly. Herein, we report the computationally designed, structurally simplified, and first solid-phase peptide synthesis of novel third-generation tubulin inhibitors in high yields. These inhibitors are devoid of tubuvaline and tubuphenylalanine fragments previously considered essential for tubulin inhibition activity. The most potent inhibitor contains four fragments arranged from the N terminal to the C terminal as N-methyl pipecolic acid, isoleucine, valine-thiazole, and asparagine. The hydrophilic tubulin inhibitors demonstrated significant anticancer activity, with IC50 values in the low nanomolar range (IC50 = 13–53 nM) within a 48 hours incubation period across prostate, lung, breast, skin, and cervical cancer cell lines. The synthetic strategy incorporates a simplified valine-thiazole ring structure, retaining both biological activity and chiral integrity of the molecules. The method enables the synthesis of potent tubulin inhibitors by avoiding multistep synthetic and purification procedures, supporting the inhibitor's applicability for large-scale synthesis and potential therapeutic development. The structural modifications at the N-terminal result in the loss of activity from nM to µM range, whereas the C-terminal modification had minimal impact on the potency.
KW - anticancer
KW - computational design
KW - microtubule
KW - solid-phase peptide synthesis
KW - tubulin inhibitor
KW - tubulysin
UR - http://www.scopus.com/inward/record.url?scp=105012147847&partnerID=8YFLogxK
U2 - 10.1002/chem.202501965
DO - 10.1002/chem.202501965
M3 - Article
AN - SCOPUS:105012147847
VL - 31
JO - Chemistry - a European journal
JF - Chemistry - a European journal
SN - 0947-6539
IS - 46
M1 - e01965
ER -