“…[1][2][3][4][5] The single-crystal X-ray structure determination 4 of duocarmycin C 2 (4, pyrindamycin A) established the relative and absolute configuration of the remote stereocenters, which through chemical interconversions 1,10 provided the absolute stereochemistry for 1-5. In the short time since their disclosure, they have been shown to exert their biological effects [1][2][3][4][6][7][8] through a characteristic sequenceselective DNA alkylation. 5,[9][10][11][12][13][14][15][16][17] Duocarmycin A (1) constitutes the most reactive and challenging member of this class of agents, and approaches to the 311 J.…”
mentioning
confidence: 99%
“…Two independent reports detailed the isolation and structure determination of the initial members of a new class of exceptionally potent antitumor antibiotics now including duocarmycin A ( 1 ), its potent ring open derivatives 2 − 5 , and duocarmycin SA ( 6 ), Figure . − The single-crystal X-ray structure determination 4 of duocarmycin C 2 ( 4 , pyrindamycin A) established the relative and absolute configuration of the remote stereocenters, which through chemical interconversions 1,10 provided the absolute stereochemistry for 1 − 5 . In the short time since their disclosure, they have been shown to exert their biological effects − ,− through a characteristic sequence-selective DNA alkylation. ,− 1 …”
Full details of an enantioselective total synthesis of
(+)-duocarmycin A (1) are described in which
a
solution to the control of the relative and absolute stereochemistry of
the remote stereocenters is provided. Catalytic
asymmetric dihydroxylation of 15 was employed to introduce
the absolute stereochemistry required for the activated
cyclopropane, and a diastereoselective Dieckmann-type condensation of
61 was employed to control the absolute
stereochemistry of the C6 quaternary center. The complementary
diastereoselectivity of a thermodynamic versus
kinetic condensation of 61 permitted the divergent synthesis
of (+)-duocarmycin A or epi-(+)-duocarmycin A
from
common intermediates. Final introduction of the reactive
cyclopropane was accomplished by transannular
spirocyclization of the mesylate 44 upon treatment with base
or directly from the corresponding free alcohol itself,
duocarmycin D1 (42), upon Mitsunobu activation.
Notably, the asymmetric dihydroxylation of 15
employing
(DHQD)2-PHAL/(DHQ)2-PHAL was found to proceed
with a reverse enantioselectivity than predicted from
established
models. Employing this approach, the key partial structures
(+)-N-BOC-DA (67) and
(+)-6-epi-N-BOC-DA (71)
and their unnatural enantiomers were also prepared, and a study of
their acid-catalyzed solvolysis reactivity,
regioselectivity (3:2), and stereochemistry is detailed. Notably,
the solvolysis reaction regioselectivity is lower than
the characteristic adenine N3 alkylation of duplex DNA, which proceeds
with exclusive nucleophilic addition to the
least substituted C8 cyclopropane carbon. This may be attributed
to the significant destabilizing torsional strain and
steric interactions characteristic of the SN2 reaction of a
large nucleophile that accompany the abnormal addition of
adenine when restricted to the minor groove bound orientation of the
reactants.
“…[1][2][3][4][5] The single-crystal X-ray structure determination 4 of duocarmycin C 2 (4, pyrindamycin A) established the relative and absolute configuration of the remote stereocenters, which through chemical interconversions 1,10 provided the absolute stereochemistry for 1-5. In the short time since their disclosure, they have been shown to exert their biological effects [1][2][3][4][6][7][8] through a characteristic sequenceselective DNA alkylation. 5,[9][10][11][12][13][14][15][16][17] Duocarmycin A (1) constitutes the most reactive and challenging member of this class of agents, and approaches to the 311 J.…”
mentioning
confidence: 99%
“…Two independent reports detailed the isolation and structure determination of the initial members of a new class of exceptionally potent antitumor antibiotics now including duocarmycin A ( 1 ), its potent ring open derivatives 2 − 5 , and duocarmycin SA ( 6 ), Figure . − The single-crystal X-ray structure determination 4 of duocarmycin C 2 ( 4 , pyrindamycin A) established the relative and absolute configuration of the remote stereocenters, which through chemical interconversions 1,10 provided the absolute stereochemistry for 1 − 5 . In the short time since their disclosure, they have been shown to exert their biological effects − ,− through a characteristic sequence-selective DNA alkylation. ,− 1 …”
Full details of an enantioselective total synthesis of
(+)-duocarmycin A (1) are described in which
a
solution to the control of the relative and absolute stereochemistry of
the remote stereocenters is provided. Catalytic
asymmetric dihydroxylation of 15 was employed to introduce
the absolute stereochemistry required for the activated
cyclopropane, and a diastereoselective Dieckmann-type condensation of
61 was employed to control the absolute
stereochemistry of the C6 quaternary center. The complementary
diastereoselectivity of a thermodynamic versus
kinetic condensation of 61 permitted the divergent synthesis
of (+)-duocarmycin A or epi-(+)-duocarmycin A
from
common intermediates. Final introduction of the reactive
cyclopropane was accomplished by transannular
spirocyclization of the mesylate 44 upon treatment with base
or directly from the corresponding free alcohol itself,
duocarmycin D1 (42), upon Mitsunobu activation.
Notably, the asymmetric dihydroxylation of 15
employing
(DHQD)2-PHAL/(DHQ)2-PHAL was found to proceed
with a reverse enantioselectivity than predicted from
established
models. Employing this approach, the key partial structures
(+)-N-BOC-DA (67) and
(+)-6-epi-N-BOC-DA (71)
and their unnatural enantiomers were also prepared, and a study of
their acid-catalyzed solvolysis reactivity,
regioselectivity (3:2), and stereochemistry is detailed. Notably,
the solvolysis reaction regioselectivity is lower than
the characteristic adenine N3 alkylation of duplex DNA, which proceeds
with exclusive nucleophilic addition to the
least substituted C8 cyclopropane carbon. This may be attributed
to the significant destabilizing torsional strain and
steric interactions characteristic of the SN2 reaction of a
large nucleophile that accompany the abnormal addition of
adenine when restricted to the minor groove bound orientation of the
reactants.
“…In the first key study (59,70,71), it was shown that 17-20 exhibited identical alkylation selectivities (5'-AA > 5'-TA) independent of their absolute configuration and identical to both enantiomers of 11 and 12. In addition, the natural enantiomers of [21][22][23][24] exhibited DNA alkylation selectivities identical to that of (+)-CC-1065 and were more selective and more efficient than [17][18][19][20] ,.-OMs (43). One unique feature of 3 is the C6 methyl ester on the left-hand side of the alkylation subunit that complements the right-hand side linking amide.…”
Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronicaily controlled adenine-N3
“…The exceptionally potent antitumour antibiotics CC-1065 (1) [1][2][3][4] and duocarmycins (2 -3) [5][6][7][8][9][10][11][12][13][14] represent a class of natural compounds, that derive their biological effects through the reversible, stereoelectronicallycontrolled sequence selective alkylation of DNA [15][16][17][18][19][20][21][22][23].…”
It is accepted that neoplastic diseases are related to gene alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA based moieties. In this field, analogues of naturally occurring antitumour agents, such as CC-1065 and/or the duocarmycins, represent a new class of highly potent antineoplastic compounds, currently under investigation. CC-1065 and duocarmycins represent a class of exceptionally potent antitumour antibiotics that derive their biological effects from the reversible, stereoelectronically-controlled sequence selective alkylation of DNA. All natural compounds showed a cytotoxicity against leukaemia L1210 cell lines in the range 10 -220pM but while CC-1065 showed a good antitumour activity in an in vivo model (optimal dose from 10 -100 µg/g), duocarmycins showed weak antitumour activity. Despite its potency, CC-1065 cannot be used in humans due to eventual fatality. For this reason many scientists have focused their attention on this class of compounds, in order to obtain new derivatives with equal in vitro potency but a better profile in in vivo models. This effect is accompanied by dramatic changes in the morphology of hepatic mitochondria. On this basis, the recent developments on SARs for this class of compounds and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature and, finally, a conclusive opinion will be given on this topic.
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