Michael J. Martinelli

Cryptophycins-309, 249 and other cryptophycin analogs: preclinical efficacy studies with mouse and human tumors.

SummaryCryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d × 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (−) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.

Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butyltin oxide†

The reaction of internal 1,2-diols with catalytic n-Bu2SnO, p-TsCl (1.05 equiv.) and Et3N (1.1 equiv.) led to selective monotosylation. In the case of cyclic substrates, the cis-1,2-diol moiety appeared best suited for optimal results, supporting the intermediacy of a five-membered chelate.

1,3-Dipolar cycloreversion of a 1,3,4-oxadiazolidine as a controlled azomethine imine surrogate for pyrazolidine synthesis

Abstract Azomethine imines were generated in a controlled manner through a thermally allowed 1,3-dipolar cycloreversion of 1,3,4-oxadiazolidines and subsequently trapped with dipolarophiles. This method results in the construction of the pyrazolidine heterocycles. A new method for the selective formation of the key semicarbazide substrate, from benzylidene hydrazone, is also disclosed.

Synthesis and biological evaluation of cryptophycin analogs with substitution at C-6 (fragment C region).

Analogs of the antitumor agents cryptophycins 1 and 8 with dialkyl substitution at C-6 (fragment C) were synthesized and evaluated for in vitro cytotoxicity against human leukemia cells (CCRF-CEM). The activity of these analogs decreased as the size of the substituents at C-6 increased. The C-6 spirocylopropyl compound (2g) was highly potent in vitro and showed excellent antitumor activity in animal models.

A novel approach for total synthesis of cryptophycins via asymmetric crotylboration protocol

Abstract Acyclic and a highly efficient stereoselective C C bond formation of aldehyde 3 with the crotylboron reagent 4 , derived from (−)-α-pinene, provided a homoallylic alcohol 6 in ≥99% enantio-(ee) and diastereomeric excess (de). The alcohol 6 was linearly converted into the desired Fragment A 10 of cryptophycins in seven steps. This enantiomerically pure Fragment A was conveniently and efficiently coupled with the other three fragments, namely B, C and D, and provided the desired cryptophycin A derivative ( LY404291 ). The terminal double bond in LY404291 was further elaborated to provide a terminal epoxide LY404292 , and cryptophycins 51 and 52 .

Synthesis of enantioenriched 4-thiazolidinone (−)-LY213829 by chemoselective benzylamide cleavage in the presence of a C-S bond

Abstract ( R )-2-Methylbenzylamine has been used to covalently “resolve” thiol acid 7 and assemble 4-thiazolidinone 8a in one step. Selective deprotection of the 2-methylbenzylamide using lithium in ammonia/THF has been achieved in the presence of a readily hydrogenolyzed C-S bond. Enantioenriched (−)-LY213829 ( 1 ) of 98% ee has been prepared by this five step route in 25% yield from aldehyde 2 .

Intramolecular Diels-Alder route to 6-oxodecahydroisoquinoline-3-carboxylates : intermediates for the synthesis of conformationally constrained excitatory amino acid antagonists

Abstract We report the preparation of a hydroisoquinoline intermediate potentially useful for the synthesis of some excitatory amino acid antagonists. The requisite stereochemistry is established by an intramolecular Diels-Alder reaction, and the absolute stereochemistry is ultimately derived from S -aspartic acid. Also reported is an efficient synthesis of methyl N -CBZ aspartate β-aldehyde.

A simple and general synthesis of 4-oxo-4,5,6,7-tetrahydroindoles via a novel intramolecular 1,3-dipolar cycloaddition approach

Abstract A general synthesis of 4-keto-4,5,6,7-tetrahydroindoles 6–12 has been achieved in two steps using a new intramolecular 1,3-dipolar cycloaddition approach in moderate yields (45–60%). The potential of this methodology is demonstrated by the synthesis of a mitomycin skeleton ( 15 ) and a topoisomerase-1 inhibitor skeleton ( 17 ).

A novel, stereoselective synthesis of cis-4a (S), 8a(R)-decahydro-6(2H)-isoquinolones from meroquinene esters

Abstract Intramolecular cyclization of N-acylated meroquinene t-butyl esters in cold H2SO4 cleanly afforded cis-4a(S), 8a(R)-decahydro-6(2H)-isoquinolones with cmnplete stereocontrol in ⪢95% yield. Formation of the meroquinene esters from cinchona alkaloid autoxidation using an improved Doering protocol was accomplished in three steps with 85% overall yield.

Reaction of cryptophycin 52 with thiols

The chemical reactivity of cryptophycin 52 towards sulfur and phosporous nucleophiles under different conditions was explored to reveal the differential reactivity of the epoxide and olefinic centers. Under basic conditions 1,4-addition to the enone is favored, while under acidic conditions the epoxide is more reactive.