Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

Abstract

A streamlined total synthesis of N(14)-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.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…C−H activation was utilized to achieve an efficient synthesis of N 14 ‐desacetoxytubulysin H (Tb1) and pretubulysin D, alongside the derivatives tubulysin BCP 330 a and cubane 330 b . The synthesized compounds were biologically evaluated with an array of cancer cell lines.…”

“…CÀHa ctivation was utilized to achieve an efficient synthesis of N 14 -desacetoxytubulysin H( Tb1) and pretubulysinD,a longside the derivativest ubulysin BCP 330 a and cubane 330 b. [422] The synthesized compounds were biologically evaluated with an array of cancerc ell lines. Notable results included the novel BCP analogue Tb14 330 a,w hich showedh igh potencies against certain cell lines such as uterine sarcoma andh uman Review embryonick idney cell line.…”

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

“…[96] 4.5. N 14 -Desacetoxytubulysin H Based on the retrosynthetic disconnections shown in Scheme 9A and employing aC ÀHactivation tactic,our total synthesis of N 14 -desacetoxytubulysin H( 224) [98] is summarized in Scheme 9B.T hus,f ragments 225 and 226 were combined in the presence of PhI(OCOCF 3 ) 2 and TMSN 3 to provide ketone 227,w hose asymmetric reduction furnished selectively hydroxy compound 228.S tandard manipulations of this intermediate led to carboxylic acid 229,w hose sequential coupling with fragments 230 and 231 proceeded smoothly to generate tripeptide 232,asshown in Scheme 9B. Fragment 233 was then introduced into the growing molecule to afford N 14 -desacetoxytubulysin Hmethyl ester (234), from which N 14 -desacetoxytubulysin H(224)was liberated through ester hydrolysis and replacement of the lost acetyl group,a s summarized in Scheme 9B.Applying the developed synthetic strategies and technologies in this program we designed, synthesized, and biologically evaluated in collaboration with our biology partners dozens of tubulysin analogues as potential ADC payloads,t wo of which (235 and 236)a re shown in Scheme 9C together with their high potencies against certain cancer or cancer-like cells.…”

The Evolution and Impact of Total Synthesis on Chemistry, Biology and Medicine

“…Because of their high potencies, these compounds are suitable as payloads for ADCs and other selective delivery systems. In an effort to optimize their biopharmaceutical properties, we developed a streamlined total synthesis of N 14 ‐desacetoxytubulysin H ( 49 , Figure ) and pretubulysin D with the intention of applying it to the synthesis of a variety of analogues for biological screening. Figure outlines our successful total synthesis of N 14 ‐desacetoxytubulysin H ( 49 , 13 steps, longest linear sequence from aldehyde H ).…”

“…The synthesis was then completed through intermediates 71 – 73 as shown in Figure . From the many analogues we synthesized and tested, Tb‐20 , Tb‐32 and Tb‐33 were among the most notable, exhibiting extremely low picomolar cytotoxicities (see Figure ). Further studies with Tb‐32 and other tubulysin analogues are continuing.…”