Synthesis and Complement Inhibitory Activity of B/C/D-Ring Analogues of the Fungal Metabolite 6,7-Diformyl-3‘,4‘,4a‘,5‘,6‘,7‘,8‘,8a‘-octahydro-4,6‘,7‘-trihydroxy- 2‘,5‘,5‘,8a‘-tetramethylspiro[1‘(2‘H)-naphthalene-2(3H)-benzofuran]

Abstract

This paper reports the synthesis and the bioassay of 4-methoxy- and 4-hydroxyspiro[benzofuran-2(3H)-cyclohexane] partial analogues (5) of the complement inhibitory sesquiterpene fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy-2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a, K-76) and its silver oxide oxidized product (1b, K-76COOH). The described target compounds represent spirobenzofuran B/C/D-ring analogues lacking the A-ring component of the prototype structure. The target compounds were evaluated by the inhibition of total hemolytic complement activity in human serum. It was observed that the structurally simplified analogue 4-methoxyspiro[benzofuran-2(3H)-cyclohexane]-6-carboxylic acid (5a) exhibited an IC(50) = 0.53 mM similar to the IC(50) = 0.57 mM that was observed for the natural product derivative 1b. Exhibiting an IC(50) = 0.16 mM, the three-ringed partial structure 6-carboxy-7-formyl-4-methoxyspiro[benzofuran-2(3H)-cyclohexane] (5k)was found to be the most potent target compound. Like the natural product, 5k appears to inhibit primarily at the C5 activation step and inhibits both the classical and alternative human complement pathways. Several other analogues inhibited complement activation in vitro at concentrations similar to those required for inhibition by the natural product 1b.

Modulators of complement activation: a patent review (2008 – 2013)

“…Several Russian patents were granted to the isolation of betulinic acid sulfate (14), disulfate and its sodium salts [191][192][193][194]. In addition, tricyclic complement inhibitor 15 was disclosed [195], as a simplified analog of the recognized inhibitor K76-COOH (16) [196][197][198][199][200].…”

Synthesis and classical pathway Complement inhibitory activity of C7-functionalized filifolinol derivatives, inspired in K-76 COOH

“…The structural analogies between filifolinol and the BCD-ring system of K-76 COOH make the former an attractive starting material for the synthesis of analogs of the latter. Simplified BCDring analogs of K-76 COOH such as 9 have demonstrated to be interestingly active [20].…”

“…HRMS (ESI) found: 437.1532 [M þ Na] þ ; C 21 H 25 F 3 NaO 5 requires 437.1546. 5.1.11. (1 0 S,3 0 S,6 0 R)-3 0 -Hydroxy-7-iodo-2 0 ,2 0 ,6 0 -trimethyl-3H-spiro [1-benzofuran-2,1 0 -cyclohexane]-5-carboxylic acid (20) The ester 16 (50 mg, 0.11 mmol) was submitted to the general procedure for the saponification of esters (Method B), furnishing 20 (41 mg, 88%), as a colorless oil. ½a 25 D ¼ þ17.8 (c 1.04, CHCl 3 ).…”

Oxyphosphonium Enolate Equilibria in a (4+1)‐Cycloaddition Approach toward Quaternary C3‐Spirooxindole Assembly

“…Derivatives of this molecular core that contain a heterocyclic quaternary spirocenter at the 3‐position of the oxindole exhibit a variety of pharmacological effects, including analgesic, [5] anticancer, [4e] antituberculosis, [4c] and antimalarial properties (Figure 1). [4g] Additionally, the 2,3‐dihydrobenzofuran heterocyclic framework has generated substantial interest due to its functionality as a potential NaV1.7 blocker in the development of anti‐leukemia chemotherapeutics [6] …”

“…[4g] Additionally, the 2,3-dihydrobenzofuran heterocyclic framework has generated substantial interest due to its functionality as a potential NaV1.7 blocker in the development of anti-leukemia chemotherapeutics. [6] Emboldened by recent successes in the development of Rh II -catalyzed (4 + 1)-cycloaddition strategies for the assembly of spiropyrrolidine oxindoles, enantioselective approaches toward spirocyclopentenyl oxindoles, and inspired by the success of phosphorus mediated (n + 1) enolate cyclizations, we sought a complementary metal-free method employing an in situ generated oxyphosphonium enolate. [7] During the course of these studies, we became acutely aware of how critical the single atom component was to the success of these efforts.…”