936691-46-2

Usage

Uses

Used in Pharmaceutical Industry:
C₃₈H₅₇N₅O₇S is used as an anti-cancer agent for its cytotoxic properties, targeting the inhibition of cell growth and potentially offering a therapeutic approach for cancer treatment.

Upstream product

• 108-24-7 acetic anhydride 
• 79069-14-0 (S)-2-<(tert-butoxycarbonyl)amino>-3-methylbutan-1-ol 
• 41447-17-0 (R)-1-methylpiperidine-2-carboxylic acid 
• 921928-01-0 (R)-perfluorophenyl 1-methylpiperidine-2-carboxylate 
• 1207472-62-5 (S,E)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-((tert-butoxycarbonyl)amino)-2-methyl-5-phenylpent-2-enoate 
• 356788-71-1 [L-(trans)]-4-[(t-butoxycarbonyl)amino]-2-methyl-5-phenyl-2-pentenoic acid 
• 7524-50-7 methyl (2S)-2-amino-3-phenylpropanoate hydrochloride 
• 244033-72-5 (4S)-4-N-tert-butoxycarbonylamino-5-phenyl-2-methyl-2-trans-pentenoic acid, ethyl ester 
• 72155-45-4 Boc-L-phenylalaninal 

Relevant academic research and scientific papers

Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads

The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues. These efforts led to the discovery of a number of novel and potent cytotoxic tubulysin analogues, providing a framework for our simultaneous report, which highlights the discovery of tubulysin-based ADCs, including use of site-specific conjugation to address in vivo stability of the C-11 acetate functionality.

Design, Synthesis, and Cytotoxic Activity of New Tubulysin Analogues

Synthesis of tubulysin analogues, containing an N-methyl substituent on tubuvaline-amide together with the replacement of either the hydrophobic N-terminal N-methyl pipecolic acid (Mep) or at both N- and C- terminal peptides with available heteroaromatic

Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly

A concise and modular total synthesis of the highly potent N14-desacetoxytubulysin H (1) has been accomplished in 18 steps in an overall yield of up to 30percent. Our work highlights the complexity-augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new tubulysin analogues.

TUBULYSIN DERIVATIVES AND METHODS FOR PREPARING THE SAME

The invention relates to novel means and methods for the synthesis of tubulysin and derivatives thereof, which find their use e.g. as cytotoxic agents in targeted drug delivery. Provided is a method for preparing a tubulysin derivative, comprising reacting compounds A, B and C in a 3- component Passerini reaction, wherein compound A is a carboxylic acid according to the general formula (A); wherein compound B is an aldehyde according to the general formula (B); and wherein compound C is an isocyanide according to the general formula (C).

DESACETOXYTUBULYSIN H AND ANALOGS THEREOF

In one aspect, the present disclosure provides tubulysin analogs of the formula (I) wherein R1, R2, R3, R4, X1, X2, X3, and A1 are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein.

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

A streamlined total synthesis of N14-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., Tb14), some with exceptional potencies against certain cell lines [e.g., Tb32 with IC50 = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure-activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.

Antibody-Drug Conjugates, Compositions and Methods of Use

Antibody-cytotoxin antibody-drug conjugates and related compounds, such as linker-cytotoxin conjugates and the linkers used to make them, tubulysin analogs, and intermediates in their synthesis; compositions; and methods, including methods of treating can

TUBULYSIN D ANALOGUES

The present invention provides novel tubulysin analogues, methods of making and methods of using such analogues and conjugates thereof. The essential features for the potent cytotoxicity of tubulysin D have been established for the first time by the synthesis and evaluation of a series of analogues. By identifying functionality that surprisingly is not necessary for activity, highly potent cell-growth inhibitors have been developed that are smaller and considerably more stable than tubulysin D.

Expedient synthesis of N-methyl tubulysin analogues with high cytotoxicity

(Chemical Equation Presented) An optimized and highly efficient synthesis of potent, bioactive N-methyl tubulysin analogues 2 and 4 has been achieved with > 40% overall yields. This synthesis represents a significant improvement over previously reported s

Design, synthesis, and biological properties of highly potent tubulysin D analogues

Ten analogues of tubulysin D were synthesized and assayed against established mammalian cell lines, including cancer cells measuring inhibition of cell growth by an MTT assay. These experiments establish for the first time the essential features for the potent cytotoxicity of tubulysin D. The activities of analogues 2 to 5 demonstrate that numerous modifications may be introduced at the C-terminus of the natural product with only modest loss in activity, while the activities of analogues 6 to 8 suggest that a basic amine must be present at the N-terminus to maintain activity. Most surprisingly, analogue 10 establishes that replacement of the chemically labile O-acyl N,O-acetal with the stable N-methyl group results in almost no loss in activity. In aggregate, these structure-activity relationships enable the design of analogues such as 11 that are smaller and considerably more stable than tubulysin D but that maintain most of its potent cell-growth inhibitory activity.