Deoxo-proline-containing tamandarin and didemnin analogs, dehydro-proline-containing tamandarin and didemnin analogs, and methods of making and using them

A compound having a structure selected from the group consisting of

• wherein:
• i) R2 and R3 are one of
• (a) R3 is selected from the group consisting of —CH3 and —H;
• and R2 is selected from the group consisting of an isoleucine side chain, a valine side chain, an alanine side chain, a norleucine side chain, a norvaline side chain, a proline side chain, a leucine side chain, a histidine side chain, a tryptophan side chain, an arginine side chain, a lysine side chain, a second fluorophore, and a substituent having the structure
• (b) R2 and R3 together are a substituent having the structure
• ii) each of R5, R6, R7, R8, and R9, when present, is independently selected from the group consisting of —H, —OH, —OCH3, —CO(C6H5), —Br, —I, —F, —Cl, —CH3, and —C2H5;
• iii) R4 is selected from the group consisting of an isoleucine side chain and a valine side chain;
• iv) X is selected from the group consisting of —O— and —NH—;
• v) Y is selected from the group consisting of —H and a hydroxyl protecting group;
• vi) R10 is selected from the group consisting of a leucine side chain and a lysine side chain;
• and
• vii) R13 is an enzyme-cleavable moiety that is cleavable by an enzyme selected from the group consisting of a carboxypeptidase, a beta-lactamase, a beta galactosidase, a penicillin V-amidase, a cytosine deaminase, a nitroreductase, an alkaline phosphatase, a beta-glucuronidase, and a catalytic antibody.

A didemnin compound having the structure

• wherein:
• i) R1 is selected from the group consisting of
• —(N-methyl)leucine-deoxo-proline,
• —(N-methyl)leucine-deoxo-proline-lactate,
• —(N-methyl)leucine-deoxo-proline-pyruvate,
• —(N-methyl)leucine-deoxo-proline-lactate-(a first fluorophore),
• —(N-methyl)leucine-deoxo-proline-lactate-glutamine-pyroglutamate,
• —(N-methyl)leucine-deoxo-proline-lactate-glutamine-cyclopentanoate,
• —(N-methyl)leucine-deoxo-proline-alanine-leucine-pyroglutamate,
• —(N-methyl)leucine-deoxo-proline-(N-methyl-alanine)-leucine-pyroglutamate,
• —(N-methyl)leucine-dehydro-proline,
• —(N-methyl)leucine-dehydro-proline-lactate,
• —(N -methyl)leucine-dehydro-proline-pyruvate,
• —(N-methyl)leucine-dehydro-proline-lactate-(a first fluorophore),
• —(N-methyl)leucine-dehydro-proline-lactate-glutamine-pyroglutamate,
• —(N-methyl)leucine-dehydro-proline-lactate-glutamine-cyclopentanoate,
• —(N-methyl)leucine-dehydro-proline-alanine-leucine-pyroglutamate, and
• —(N-methyl)leucine-dehydro-proline-(N-methyl-alanine)-leucine-pyroglutamate;
• ii) R2 and R3 are one of
• (a) R3 is selected from the group consisting of —CH3 and —H;
• and R2 is selected from the group consisting of an isoleucine side chain, a valine side chain, an alanine side chain, a norleucine side chain, a norvaline side chain a leucine side chain, a histidine side chain, a tryptophan side chain, an arginine side chain, a lysine side chain, a second fluorophore, and a substituent having the structure
• (b) R2 and R3 together are a substituent having the structure
• iii) each of R5, R6, R7, R8, and R9, when present, is independently selected from the group consisting of —H, —OH, —OCH3, —CO(C6H5), —Br, —I, —F, —Cl, —CH3, and —C2H5;
• iv) R4 is selected from the group consisting of an isoleucine side chain and a valine side chain;
• v) X is selected from the group consisting of —O— and —NH—;
• vi) Y is selected from the group consisting of —H and a hydroxyl protecting group;
• and
• vii) R10 is selected from the group consisting of a leucine side chain and a lysine side chain.